Undergraduate Research Program
Krittika D’Silva – Bioengineering, Computer Engineering
Krittika is a senior at UW where she is pursuing a double degree in Computer Engineering and Bioengineering. Her current research is a collaborative project with both departments. Her work is focused on using technology as a tool in low-income regions to improve remote health monitoring and disease detection.
The motivation for the work is that diagnostic tests routinely administered in well-equipped clinical laboratories are often not appropriate for low-resource settings. However, paper-based diagnostic tests present an inexpensive and reliable diagnostic tool. Her research project consists of the development and analysis of an Android application that enables the diagnosis of paper-based tests on a mobile device. The software interprets test results using computer vision algorithms run on a mobile device and provides health workers with an objective and automated diagnosis at the point of care.
Last summer, Krittika worked as a research intern at Microsoft Research on a project similarly targeted at low-income regions. She designed and developed an Android application as part of a campaign to help end the Maoist conflict in India by giving a voice to tribal populations and facilitating communication with different agencies. The application is actively being used throughout the Chhattisgarh area in northern India.
In the future, Krittika hopes to pursue a PhD in Computer Science. Her interests lie at the intersection of Bioengineering and Computer Science where software is used as a tool to develop solutions in healthcare.
Mentor: Gaetano Borriello, Computer Science and Engineering
Project Title: Automated Analysis of Paper-Based Lateral Flow Tests on Mobile Devices
Abstract: Currently, disease detection in rural areas of developing countries is hampered by a lack of accurate, convenient and affordable diagnostic tests. The primary purpose of this research is to design and analyze software to diagnose immunoassay tests for MRSA, a bacterial infection prevalent throughout the world, on a mobile device. The tests would be paper-based and therefore cheap and appropriate for use in developing counties. Further, the software would be simple to use and intuitive and would not require a health worker to have prior training. An Android application will be developed that will allow the user to take a photo of an immunoassay test and will then interpret the test results using computer vision algorithms run on the mobile device. It will aim to provide a health worker with an objective, automated, and accurate diagnosis for MRSA at the point of care.
Ryan Groussman – Biology (Molecular, Cellular & Developmental
Biomolecular systems with global-scale impacts are Ryan’s primary area of interest. This passion drew him to the lab of Ginger Armbrust to study marine phytoplankton, the key drivers of many biogeochemical processes. Ryan aims to use molecular biology techniques in conjunction with in silico bioinformatic tools to look ‘under the hood’ at phytoplankton-driven processes. His first project at the Armbrust Lab, in the UW’s Center for Environmental Genomics, used comparative transcriptomics to investigate the evolutionary history and distribution of iron metabolism genes in marine diatoms. Currently, he’s embarking on an exciting new project to uncover the biochemical pathways involved in CO2-sensing and response in the model diatom, Thalassiosira pseudonana. Ryan is majoring in Molecular, Developmental and Cellular Biology with a minor in Oceanography. After graduating, he’s looking forward to continuing research while working toward a PhD in Biological Oceanography. Outside of academics, Ryan enjoys camping, bicycling and meditation.
Mentor: Virginia Armbrust, Oceanography
Project Title: Investigating Cyclic AMP as a Mediator of the CO2 Response in the Diatom Thalassiosira pseudonana
Abstract: Anthropogenic CO2 emissions since the Industrial Revolution have increased atmospheric CO2 concentrations to 400ppm, with an estimated increase to 800ppm by 2100. Approximately half of CO2 emissions are absorbed into the oceans, where 50 Pg C/year is taken up by marine phytoplankton. The most productive group of phytoplankton is the diatoms, which are estimated to account for 40% of marine primary production. The response of diatoms to increasing CO2 is a critical factor to consider in modeling biogeochemical changes in the ocean. Recent full transcriptome analysis of the model diatom Thalassiosira pseudonana grown under elevated CO2 has identified several genes that are significantly correlated to extracellular CO2 concentrations, including a carbonic anhydrase gene, delta-CA3, thought to be important for concentrating carbon. Research on a distantly related diatom, Phaeodactylum tricornutum, has suggested that CO2 sensing is moderated by the secondary messenger, cyclic AMP (cAMP), which regulates the expression of a carbonic anhydrase gene, ptCA1. We hypothesize that cAMP is also a key intermediate messenger in the regulation of CO2 -responsive genes in T. pseudonana, particularly delta-CA3. To test this, we will be implementing semi-continuous batch-cultures of T. pseudonana. Experimental treatments will be facilitated in a two-by-two matrix of two CO2 levels (400ppm and 800ppm) with and without treatment with 1.0 mM of 3-isobutyl-1-methylxanthine (IBMX), which raises intracellular cAMP concentrations by inhibiting the phosphodiesterase that facilitates cAMP degradation. Differential transcription of CO2-correlated genes will be measured with qRT-PCR. We anticipate reduction of cAMP-regulated transcripts and increased intracellular cAMP under IBMX and elevated CO2 treatments. The results of this research will be important in clarifying the role of cAMP in CO2 -response in diatoms. The diatom response to increasing CO2 is a critical factor in considering the flux of CO2 in the ocean.
Gina Hansen – Bioengineering
Gina’s research involvement began in high school, conducting research on crayfish sensory perception at the University of Maryland and at her high school in Virginia. Her desire to pursue research with more depth and impact on human health led her across the country to Seattle, where she is currently a junior in the Department of Bioengineering at the University of Washington. In her first quarter at the university, she joined Dr. Daniel Ratner’s laboratory in the Department of Bioengineering, where she became involved in the development and demonstration of real-time, label-free silicon photonic biosensors for phenotypic characterization of blood. With the support of the Levinson Emerging Scholars Program, Gina is investigating the adaptation of this biosensing platform to blood antigen systems beyond ABO blood type. After completing her undergraduate studies, Gina plans to gain experience in the biotechnology industry prior to attending graduate school and hopes to ultimately work in the research and development of diagnostic methods. Gina is indebted to her mentors Dr. Daniel Ratner, Dr. James Kirk, and Pakapreud Khumwan for their continued guidance and encouragement. She would like to thank Dr. and Mrs. Arthur D. Levinson for their support in her research and professional endeavors.
Mentor: Daniel Ratner, Bioengineering
Project Title: Kell Phenotyping of Processed Red Blood Cells by Silicon Photonic Biosensors
Abstract: A global need has been identified for rapid and efficient methods of extended blood typing in transfusion medicine. Today, the ABO and Rh (+/-) blood group systems are the only antigens typed in routine clinical procedures; in multiply transfused patients, repeated mismatch of the 26 additional blood group systems poses a serious risk in immune sensitization. The tedium and cost of extended blood typing prohibit the widespread implementation of typing beyond ABO and Rh. The Kell antigen has been identified as the most clinically relevant protein blood group system which is not routinely identified in the United States. We propose the design, characterization, and demonstration of a silicon photonic microring resonator platform functionalized for direct Kell typing of processed red blood. This will be accomplished in three stages: (1) Modification of the silicon microring resonator chip with anti-K antibodies: Anti-K monoclonal antibodies will be covalently bound to the silicon microring resonator surface via a scheme using Solulink’s HyNic-4FB bioconjugation linkers. (2) Determination of Kell antigenicity of ghost red blood cells (RBCs): Active ABO antigen function on ghost RBCs has been demonstrated by our prior work on the ABO-functionalized silicon photonic platform, and structural similarity between the Kell and ABO antigens indicates that Kell bioactivity is likely also retained after the ghosting process. The Kell phenotype of unprocessed and ghost RBC samples will be confirmed via routine agglutination techniques for Kell RBC phenotyping. (3) Demonstration of Kell-specific biosensing on the complete platform: Ghost RBCs will be directed over the anti-K functionalized microring resonators; the silicon photonic platform allows real-time observation and quantification of binding activity as Kell-positive ghost RBCs are captured on the microring surface. Continued work in developing rapid techniques for identification of extended RBC phenotypes has potential to make clinical transfusion procedures markedly safer.
Jane Kwon – Biochemistry, Biology (Molecular, Cellular & Developmental)
Jane Kwon is a senior in the Department of Biochemistry. She joined Dr. Kaeberlein’s lab during her freshman year with an interest in aging and neurodegenerative diseases. Starting as a yeast dissector, she helped to collect and quantify Replicative Lifespan Data of S. cerevisae. She then shifted her focus onto the role of mitochondrial health in aging using small nematodes, C. elegans, as a model system. With a strong background in biochemistry and molecular biology techniques, Jane is interested in applying her scientific knowledge to clinical settings. She aspires to become a physician who can actively participate in the development of therapies and bridge the gap between the scientific community and patients through education. Outside of lab, Jane enjoys mentoring and teaching fellow undergraduate students with interests in science and medicine. Jane would like to thank her mentors, Dr. Kaeberlein and Chris Bennett for their support throughout her undergraduate career, as well as the Levinson Emerging Scholars Program for enabling her to continue her research project.
Mentor: Matt Kaeberlein, Pathology
Project Title: Investigating the Role of Mitochondrial Unfolded Response in Aging and Health
Abstract: Mitochondria, the energy producing organelles in eukaryotic cells, play a critical role in cell metabolism, and mitochondrial dysfunction has been implicated in a variety of diseases ranging from severe childhood disorders to age-associated neurodegenerative diseases such as Alzheimer’s disease. The goal of my research project is to define the mechanisms by which cells sense and respond to mitochondrial dysfunction in order to promote healthy aging, using Caenorhabditis elegans as a model system. The mitochondrial unfolded protein response (UPRmt) is a mitochondrial stress signal that regulates the expression of several nuclear-encoded mitochondrial genes, including chaperones and other factors that assist in folding of misfolded or aggregated proteins in the mitochondria. While researches suggest a link between the UPRmt and aging, the role of the UPRmt signaling in health is yet to be characterized. In order to fully understand how mitochondrial stress and the UPRmt affect aging process of C. elegans, I am performing a genome-wide RNAi screen to identify genes that attenuate the induction of the UPRmt in response to mitochondrial stress. Once the components of the UPRmt signaling cascade are identified, I will determine the role of the UPRmt and mitochondrial protein homeostasis on longevity by measuring lifespan and health span, the amount of time in healthy and productive state. Understanding the genetics behind the UPRmt and protein homeostasis has enormous benefits to health, especially regarding mitochondrial and age-related diseases, such as neurodegenerative diseases and cancer.
Will Lykins – Bioengineering: Nanoscience & Molecular Engineering
Unbeknownst to him, Will Lykins has always been interested in engineering. He spent the majority of his childhood building Lego castles and Sand fortresses, although he didn’t connect that to engineering until later. Will also had an early passion for the preforming arts and music. In high school Will worked as a light designer for the school musicals. There he learned that small changes can have dramatic impacts on the larger product. Will, again unknowingly, became fascinated with molecular engineering; where changing the smallest atomic structure can revolutionize technology. Will has also fostered a lifelong interest in medicine. As a type one diabetic, Will has always had a finger on the pulse of medical innovation. Upon entering the University of Washington, Will discovered the department of Bioengineering and simultaneously discovered a way to unite all of his passions. Instead of building well-lit sand hospitals, Will now works in the Woodrow Laboratory, where he has the opportunity to use molecular engineering techniques to build new vaccines and treatments for HIV. In addition to research, Will spends a lot of his time in the classrooms of K-12 students, clarifying and expanding hands-on STEM education. After graduation, Will hopes to pursue a PhD in Bioengineering, to continue engineering revolutionary molecular medicines.
Mentor: Kim Woodrow, Bioengineering
Project Title: Cross-linked Lipid Particles for Delivery of Antiretroviral Combinations to Inhibit HIV Infection
Abstract: The global burden of HIV exceeds 30 million individuals, who are predominantly in low resource regions. While the treatment of HIV has been dramatically improved by the advent of combination antiretroviral therapies there is a clinical need for improved delivery systems that enable the realization of drug combinations with enhanced potency and lower toxicity that can also address the emergence of drug resistance. Delivery systems are needed to enable the combination of small molecule antiretroviral drugs (ARV), which span a wide range of physiochemical properties that precludes their easy co-delivery. Additionally, there are currently no available delivery systems for easy combination of ARV drugs and antiviral biologics such as proteins and nucleic acids. In this study, we investigate the use of cross linked lipid particles (CLPs) for the delivery of physico-chemically diverse small molecule antiretroviral drugs in combination with potent antiviral neutralizing proteins against HIV-1. We have demonstrated successful synthesis of the CLP platform via DLS analysis and cryo-transmission electron microscopy. Using the CLP platform, we have achieved loading of raltegravir, an integrase inhibitor (hydrophilic), and etravirine, a non-nucleoside reverse transcriptase inhibitor (hydrophobic).We also demonstrate the surface conjugation of antiviral proteins such as cyanovirin-N and HIV-1 neutralizing antibodies. All CLPs show uniform size, significant small molecule drug loading, and efficient antiviral protein conjugation. The triple agent CLP shows minimum cytotoxicity and potent antiviral activity against HIV-1 BaL infection of TZM-bl cells in culture. We also demonstrate antiviral activity of the triple agent CLP against HIV-1 viral resistant isolates. Our results demonstrate the robustness of CLPs as a delivery platform for antiretroviral combinations, including small molecules and biologic therapeutics. We have demonstrated the activity and synergy of all individual components in the particle system. This platform could be leveraged as a treatment to eliminate viral reservoirs in vivo.
Karl Marrett – Neurobiology
Karl Marrett is a junior majoring in Neurobiology with departmental honors and minoring in applied math. He is also a Mary Gates Leadership Scholar and a Mortar Board Alumni Scholar. He came from a research background in ecology and plant physiology, and worked in public and global health research at Battelle in Seattle. He is currently working with Professor Adrian KC Lee on designing a high bit-rate auditory P300-based brain computer interface (BCI) for both clinical and commercial applications. He worked on this project as part of the Center for Sensorimotor Neural Engineering summer exchange with the Brain Links Brain Tools Cluster in Freiburg Germany. In relation to this project, he attended the 6th International BCI Conference and has presented his work at the Computational Neuroscience Connection 2014. The Computational Neuroscience Training Program and involvement with the Center for Sensorimotor Neural Engineering has motivated Karl to pursue research that brings together basic neuroscience research and engineering to spark applications in neurotechnology. He is interested in continuing his academic education in a graduate program where he can pursue these interests. Karl would like to thank his mentors Dr. Adrian KC Lee, Dr. Michael Tangermann, and Mark Wronkiewicz for their guidance on the project. He is also deeply grateful to Dr. and Mrs. Levinson for their support.
Mentor: Adrian KC Lee, Speech & Hearing Sciences
Project Title: Optimizing Performance in an Auditory P300-Speller
Abstract: In order to communicate, patients with total loss of muscle control can rely on brain computer interfaces (BCI) that utilize the P300 response and evoked related potentials of the brain recorded using electroencephalography. Typically, P300 spellers rely on selective visual attention to evoke characteristic electrophysiological responses to flashing letters on a computer screen. However, due to the auditory system’s acute ability to selectively attend an auditory stream in what is known as the “cocktail party effect,” new speller paradigms that aid listeners’ ability to selectively attend can potentially increase the maximum bitrate of communication for auditory-based spellers. This project is focused on advancing auditory BCIs and then evaluating new designs by measuring the cognitive load of users. The experiment tests the cognitive load of each condition via pupillometry (since changes in pupil dilation correlate to the cognitive load of a task) and a survey gauging the relative task load. By quantifying the cognitive load of different variations of the auditory task, this project offers future possibilities for auditory systems to help improve the ease of use and practicality for the community of individuals who rely on P300 speller systems as well as better evaluate other common BCI strategies.
Sean Murphy – Bioengineering, Economics
Sean Murphy is a senior in the Departments of Bioengineering and Economics. Sean joined Professor Michael Laflamme’s lab in his freshman year and has worked under the supervision of Dr. Scott Lundy. The Laflamme lab investigates the use of stem cells for cardiac repair. He was drawn to cardiovascular regenerative medicine by the potential impact of new therapies. His first project focused on the quantification of Ribonucleotide Reductase (RR) in stem cell-derived cardiomyocytes overexpressing RR that were grafted into rat hearts. Sean’s current research examines the off target effects of rotigaptide on early stage stem cell-derived cardiomyocytes. This research provides a critical step in translating rotigaptide research into clinical treatment. Over this past summer, Sean interned in the Chemistry Group at Seattle Genetics where he worked on evaluating anticancer antibody drug conjugates through enzyme activity and intracellular drug concentration. He plans to continue to pursue his passion for biomedical research by pursuing a PhD. Sean has participated in several outreach organizations and cofounded STEM Mentors. Outside of the lab, Sean works on a Bioengineers Without Borders project and plays on the UW men’s ultimate frisbee team.
Mentor: Michael Laflamme, Pathology
Project Title: Rotigaptide Modulation of Pluripotent Stem Cell-Derived Cardiomyocyte Maturation and Proliferation
Abstract: Cardiovascular disease is the leading cause of death worldwide, and current treatments for heart failure are limited to slowing the disease progression or transplanting a donor heart. One potential approach to restore heart function is to transplant human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs). Anti-arrhythmic peptides such as rotigaptide are a promising strategy for electromechanical coupling as grafts can be functionally blocked from the host by uncoupled gap junctions. However, rotigaptide may also modulate other parameters such as graft cell viability and proliferation, so my research goal is to screen for such “off-target” effects through in vitro studies. We hypothesize that rotigaptide treatment will not affect proliferation or maturation of early stage hPSC-CMs. To test this hypothesis, immature hPSC-CMs will be treated with either rotigaptide or a scrambled control peptide. To compare proliferation in rotigaptide-treated versus controls, cultures will be pulsed with the thymidine analogue BrdU and detected by immunocytochemistry. Rotigaptide might cause deleterious effects by opening unjunctioned connexons that could lead to cell death through ATP loss or calcium overload. A live/dead assay has been shown to identify apoptotic cells to quantify cell viability and correlate this with connexin expression and phosphorylation status. This investigation will provide a basis for identifying modulation of parameters such as graft cell viability, maturation, and proliferation due to long term rotigaptide treatment.
Milan Vu – Biology (General)
Milan Vu is currently a senior pursuing a degree in Biology. Having an interest in the sciences since high school, her curiosity about scientific research and desire to connect with her academic program at a deeper level led her to join the lab of Dr. Keiko Torii during her sophomore year. As a whole, the Torii lab studies the coordination and signaling processes controlling differentiation of plant epidermal stem cells into their mature state as stomata. Milan’s research focuses on a new direction in this area by using a reverse genetics approach to characterize unexplored genes that appear to be involved in stomatal development. Thanks to the support of the Levinson Emerging Scholars Program, Milan is excited to see her project through to completion and hopes to present her finalized data prior to graduation in the spring. Besides research, Milan also spends her time mentoring students with the UW Dream Project and aspires to combine her passions for service and science in her future career.
Mentor: Keiko Torii, Biology
Project Title: Exploring the Role of Receptor-Like Kinases in Plant Epidermal Development
Abstract: Stomata are pore-like structures on plant epidermis responsible for regulating gas exchange and respiration processes. The development of stomata is tightly controlled through various signaling pathways. Among the structures involved are receptor-like kinases (RLKs), proteins characterized by an extracellular domain, transmembrane region, and a cytoplasmic kinase domain. In Arabidopsis, receptor-like kinase genes account for nearly 2.5% of protein coding genes and are known to have broad roles in signaling and cell differentiation. However, few studies have identified specific biological functions of these many RLKs and their mechanisms of action. Previously, our group took advantage of genetic resources that specifically enrich stomatal precursor cell state and performed transcriptomic analysis (Pillitteri et al. 2011 Plant Cell). Based on the transcriptome data, we selected three RLKs, tentatively named MV1, MV2, and MV3, that are highly expressed in stomatal precursors. In order to explore their function we have generated transgenic plants expressing MV1, MV2 and MV3 under the control of their respective promoters carrying c-terminal yellow fluorescent protein (YFP) tags. Preliminary screening of the first-generation YFP transgenic lines has shown that all genes are expressed in the epidermis of young developing tissue, confirming their annotated expression patterns. Furthermore, MV1 is enriched in undifferentiated stem cell-like epidermal precursors whereas MV3 appears enriched in discrete locations in the membrane of stomatal precursor cells. In order to explore the function of these RLKs we are generating lines expressing kinase domain ATP-binding site mutants. We expect the mutations to interfere with signaling networks in which the kinases are involved and to incur a dominant negative mutation within each respective RLK, thereby providing a quantifiable phenotype for future measure.
Cindy Wei – Biochemistry
Cindy Wei is a senior majoring in Biochemistry (BS) and minoring in Global Health with Departmental Honors in Biochemistry. Her interest in biochemistry stems from a high school science camp project in New Zealand, where she grew up. In her last three years studying abroad at UW as a biochemistry student, she was most captivated by the experimental details explained in classes and she wanted to apply techniques learned in a classroom to a cutting edge research topic. In her junior year she joined the Hoppins lab in the Department of Biochemistry, working on the molecular characterization of mitochondrial movement. Her current project focuses on the expression and purification of the proteins involved in microtubule directed mitochondrial transport: Trak1/2 and Miro1/2. Once these recombinant proteins have been obtained she will rebuild the transport machinery in vitro to investigate the function of each protein and their effects on each other in a simple system. Her undergraduate research experience has inspired her to continue to be involved in research and to go on to pursue a PhD after graduation in June 2015.
Mentor: Suzanne Hoppins, Biochemistry
Project Title: Molecular Characterization of Mitochondrial Movement
Abstract: Mitochondria are best known for their roles in cellular energy metabolism, but are also required for the synthesis of lipids, pyrimidines and iron sulfur clusters, and play a role in cell cycle progression and cell death. Given the plethora of essential cellular activities that require mitochondrial function, it is not surprising that defects in mitochondrial function are implicated in many different human diseases and disorders including neurodegenerative disorders, diabetes, cancer and myopathies. Mitochondria are dynamic and the integrated activities of mitochondrial fusion, division and transport are regulated to adjust the shape of the organelle, which in turn affects mitochondrial functions. Mitochondria move along microtubule tracks in cells and, in addition to a role for movement in mitochondrial fusion and division, this activity is also essential for mitochondrial distribution in cells, which is particularly important in neurons where mitochondria must move from the cell body to the axon. Although proteins that participate in mitochondrial movement have been identified, relatively little is known about how they assemble into a complex and what regulates the activity of the complex. Exploring the biochemical properties of the mitochondrial transport complex will provide insight into the mechanism of mitochondrial movement and possible forms of regulation in cells. Our goal is to obtain recombinant purified mitochondrial transport proteins. We will start with fundamental biochemical characterization of their properties such as relative affinities and stoichiometry to determine how the complex assembles in cells. Ultimately, we would like to reconstitute movement so that we can also study the relative forces generated by these molecular machines and how that force is changed to gain insight into the regulation of mitochondrial movement. Understanding mitochondrial movement will give us a different perspective and insight into the molecular basis of many human diseases and disorders, especially those involving neuron defects.
Wenbi Wu – Biochemistry, Chemistry
Wenbi Wu is a senior in Biochemistry (BS), Chemistry (BS) and Mathematics (minor) with Departmental Honors in Chemistry and Biochemistry. Starting from her freshman year, Wenbi began doing research in the lab of Professor David Ginger. Her research area is in hybrid polymer/quantum dot solar cells, with a current research focus on morphology in hybrid polymer/quantum dot solar cells treated with different quantum dot surface ligands. In collaboration with the Moule group at UC Davis, she is trying to obtain detailed three-dimensional tomography images. The goal is to better understand and control morphology in these films to optimize the solar cell performance. Wenbi would like to thank her wonderful mentors Prof. Ginger and Adam Colbert. She would also like to thank the Levinson Scholarship for the support. As an undergraduate research leader, Wenbi is also very interested in engaging more students, especially international students, in undergraduate research.
Mentor: David Ginger, Chemistry
Project Title: Understanding Morphology in Hybrid Polymer/Quantum Dot Solar Cells Treated with Various Ligands
Abstract: Solar technology is a potential way to help meet the growing demand for clean, renewable energy. Hybrid composites of inorganic quantum dots, with organic semiconducting polymers offer a potential means of producing low-cost, solution-processable photovoltaics. The synthesis of quantum dots typically involves the use of large surfactant molecules to facilitate particle growth and solubility. These native ligands act as electrical insulators that impede charge transport in photovoltaic devices. Therefore, it is necessary to exchange these large ligands with small molecules to achieve efficient charge carrier photogeneration and transport. In this research, we will examine the role of morphology in bulk heterojunction blends of low band gap PbS quantum dots with the conjugated polymer poly((4,8-bis(octyloxy)benzo(1,2-b:4,5-b’)dithiophene-2,6-diyl)(2-((dodecyloxy)carbonyl)thieno(3,4-b)thiophenediyl)) (PTB1) treated with different ligands including halide ions and organic crosslinkers. We predict that these linkers will alter both the electronic properties of the polymer/quantum dot interface, as well as the 3D connectivity (or morphology) of the polymer/quantum dot blend film. By using photoinduced absorption and transient photovoltage techniques, we will study long-lived charge generation and recombination kinetics of our devices with different ligand treatments. My preliminary data indicates that the ligand treatments exhibiting higher device performance correlate to longer carrier recombination lifetimes. So far, however, understanding of morphology has been a critical missing variable in these devices. By synthesizing PbS quantum dots and preparing blends with different ligand treatments for characterization using high angle annular dark field electron tomography (HAADF-ET) in collaboration with the Moule group at UC Davis, we will try to obtain detailed three-dimensional tomography images. This project will give us a better understanding and control of morphology in these films which can be used to optimize the performance of hybrid quantum dot/polymer photovoltaics.
Derek Britain – Biochemistry, Bioengineering
Derek Britain is a senior in the Departments of Bioengineering and Biochemistry. He got his first exposure to research his freshman year when he joined Dr. Deok-Ho Kim’s lab in Bioengineering. While there, Derek worked on creating a novel cell culture device that combined a nano-patterned substrate with a microfluidic gradient system for the organization of stem cells into cardiac tissue grafts. While testing his device, he became fascinated with how the stem cells were able to sense and respond to the substrate and chemotaxic gradient. Derek continued to pursue his interest, and at the start of his junior year join Dr. Roger Brent’s lab at Fred Hutchinson Cancer Research Center. Using budding yeast as a model organism, Derek now researches how cells gather information from their environment, how this information is processed by the cell, and how a cell makes a decision based on the results. Currently, he is investigating the role microtubule end binding proteins play in signal transmission and fidelity. Derek is also investigating mutant forms of these proteins found in the human population, and if these mutations result in poor signal handling that could result in poor cell decisions. After completing his undergraduate degrees Derek plans to further pursue his research in a Systems Biology PhD program.
Mentor: Roger Brent, FHCRC
Project Title: The effects of human variants of yeast Bim1 on signaling in the yeast pheromone response pathway
Abstract: The three mammalian MAPRE proteins (EB1, RP1, and EBF3) play important roles in the stability and localization of microtubules, and facilitate the binding of other proteins to microtubule plus ends. The 1000 Genomes Project and The Exome Sequencing Project have elucidated non-conservative coding sequence allelic variants of the MAPRE proteins in the human population. Disruption of MAPRE protein function could decreases signal fidelity and microtubule function, leading to poor cell decision making and mitotic chromosome separation. The MAPRE proteins are related by descent from a common ancestor to the Bim1 protein in budding yeast. By designing and building mutated versions of Bim1 that contain mutations corresponding known MAPRE allelic variants and expressing them in yeast, we hope to elucidate the effects of the MAPRE polymorphisms. In particular, we will observe changes in signaling fidelity in the yeast pheromone response pathway. Budding yeast will be exposed to a linear gradient of mating pheromone, and various florescent reporters will be monitored through live-cell epi-fluorescent and FRET microscopy. Florescent signals will be quantitatively analyzed to determine protein abundance, indicating the degree to which signal fidelity has been affected. Adverse effects on signal fidelity can result in poor decision making and environmental response, potentially leading to the generation of disease. By better understanding the effects of allelic variants in the human population, we will be able to develop individualized health plans and therapies.
Cara Comfort – Bioengineering, Neurobiology
Cara Comfort is a senior double majoring in Bioengineering and Neurobiology. Since her first year at UW, she has been actively immersed in research. As she was interested to find a way to integrate her two majors, she joined Bill Moody’s cortical development lab the summer after her sophomore year. There she enjoys the combination of creative stimulation inherent in experimental design as well as the mathematical challenges demanded by MatLab and scientific analysis. Through her senior capstone project, Cara plans to synthesize the skills developed in both her majors to help elucidate the complex mechanisms behind cortical development, an area she has grown very passionate about. After graduating UW, she intends to pursue a Ph.D. in neural engineering, preferably continuing her research in the field of neurodevelopment. Cara is extremely grateful for the support by Dr. and Mrs. Arthur D. Levinson on her current interdisciplinary research project.
Mentor: William Moody, Biology
Project Title: A computational model of GABAergic cells to elucidate initiation of SSA in developing mouse cortex
Abstract: It is poorly understood how cortical connections are established in the brain during development. In the past decade, it was established that waves of synchronous spontaneous activity (SSA) are essential for developing the proper circuitry in the neonatal mouse cortex. These waves of electrical activity, involving a vast number of neurons firing bursts of action potentials simultaneously, produce transient increases in intracellular calcium concentration, which can be imaged with calcium-sensitive fluorescent dyes. The Moody lab recently determined that during early developmental stages, waves of SSA originate from the ventral piriform cortex and are dependent on GABAergic transmission. Since developmental problems may arise when these wave fail to initiate at the proper time, it is crucial to determine exactly how SSA is initiated. My research project aims to 1) identity the exact subpopulation of GABAergic cells that generate SSA and 2) determine what combination of intrinsic physiological properties and synaptic connectivity defines the pacemaker population. In particular, I will estimate key system and cellular parameters that define GABAergic networks using past experimental data. Then, I will build a computational model of GABA pacemaker cells in MATLAB that simulates wave initiation and propagation, implementing the previously estimated parameters in the model. By matching the simulated wave propagation frequency and speed to those determined by experimental data, I will gain insight into the parameter spaces of cell connectivity and integration time, which are difficult to estimate given the current data. Finally, I will attempt to validate the model by first estimating more realistic values of these parameters via patch clamp experiments, and then comparing these obtained values to the parameter spaces calculated by the model.
Jennifer Gile – Neurobiology
Jennifer Gile is a senior majoring in Neurobiology. She transferred from the Johns Hopkins University after her freshman year. She works in the de la Iglesia laboratory, which focuses on the pathways by which the central nervous system controls the timing of behavior and physiology. Her area of research is in circadian biology, with a current research focus on the circadian modulation of neuromotor control. The goal of this research project is to understand how the circadian system regulates the primary motor cortex programs. This will be essential for the design of BCI (brain computer interface). Jennifer is a Gates Millennium Scholar who makes several trips back to her old high school in Idaho to educate diverse populations of students about the scholarship and inspire them to realize the value of a college education. Jennifer would like to thank her wonderful mentors Dr. De la Iglesia, Dr. Smarr, Dr. Chizeck, and Oliver Johnson. She would also like to thank the Levinson Scholarship for the support. All of this would not be possible without their support. She is planning on pursuing an M.D./Ph.D. upon graduation in Winter 2015.
Mentor: Horacio de la Iglesia, Biology
Project Title: Circadian Modulation of Neuromotor Control
Abstract: The circadian system controls daily rhythms of behavior and physiology, including locomotor activity and motor-task performance. The master regulation of these rhythms is achieved by a circadian clock located in the suprachiasmatic nucleus of the hypothalamus; however, it is not clear how motor tasks are programmed by the motor cortex at different times of the day. Our hypothesis is that similar motor tasks executed at different times of the day may require different motor programs to account for the daily variance introduced by the circadian system. How and where in the brain this variance in motor control manifests has not been established. We propose to identify specific primary motor cortex activity patterns associated with specific motor outputs across the 24-hour day. We implant electrocorticographic (ECoG) electrodes onto the motor cortex of mice and record brain wave activity during wheel running and rest. We first test whether the motor cortex may show a brain-wave signature for wheel running, and second whether this signature may change predictably across the 24-hour day. Initial results indicate a broad-spectrum power increase in brain-wave output from the motor cortex associated with wheel running. Furthermore, there appears to be a circadian modulation of the power of specific ECoG frequencies. The decoding of motor cortex signals is at the core of the design of brain-machine interfaces (BMIs). These devices decode signals from the conscious brain to drive the execution of specific tasks by a machine, such as an artificial limb. Our work will directly contribute to our understanding of how the motor cortex decodes circadian time. This knowledge is essential to create BMIs that can operate effectively throughout the 24-hour day to execute tasks by brain-operated artificial devices.
Nicolette McCary – Biology, Oceanography
Biology and the Ocean have inspired Nicolette from a very young age, as she was raised spending most summer and weekend days on the beaches of Puget Sound. She was always fascinated by the barely perceptible organisms in tide pools, wondering what they were. After being invited to join Dr. Gabrielle Rocap’s Environmental Genomics Lab in the department of Oceanography her sophomore year, she was able to spend two years researching marine viruses and phytoplankton. She hopes to contribute to the limited knowledge of diatom virus seasonality, and identify Pseudo-nitzschia hosts that can be used to effectively isolate viruses in the future. After graduating with a degree in Oceanography (BS), she plans to remain engaged in research through the realm of scientific outreach. Her dream is to work with the younger generation, involving them in exciting scientific opportunities. In her spare time she loves to swim and volunteer with children at her church.
Mentor: Gabrielle Rocap, Oceanography
Project Title: Exploring host permissivity and the seasonality of viruses that infect the diatom Pseudo-nitzschia
Abstract: Diatoms are unicellular photosynthetic algae, or phytoplankton, and account for approximately 20% of global primary production. The pennate diatom Pseudo-nitzschia can produce a neurotoxin called domoic acid (DA) that builds up in the tissues of shellfish when this diatom blooms. DA poisoning causes life-threatening conditions in mammals and humans when these shellfish are ingested. One mechanism of bloom regulation that we know little about is that of viral infection, despite viruses being the most abundant predator in the ocean. One Pseudo-nitzschia infecting virus, the PmDNAV, was isolated in 2009. I hypothesize that there are many different viruses that can infect diatoms of the genus Pseudo-nitzschia in addition to the PmDNAV. In order for future researchers to be successful in Pseudo-nitzschia virus isolation, I am studying the seasonality of Pseudo-nitzschia viruses and finding permissive hosts to isolate them with. A permissive host is more susceptible to viral attack, and thus is more effective to use when isolating viruses. There have only been two studies on diatom virus seasonality, neither of which addresses the Pacific Northwest or Pseudo-nitzschia. To get a systematic look at virus seasonality, I am sampling the viral community once a month at two locations: Gray’s Harbor off the Washington Coast, and Penn Cove in the Puget Sound. I started in April 2013, and will continue for the full year. At each location I take water samples for concentrating viral particles, and a net tow of the planktonic community for Pseudo-nitzschia isolation. I am using infection experiments to determine viral presence, while also determining host permissivity. No one else in the science community is studying Pseudo-nitzschia viruses, with very few studying diatom viruses at all. After my data is published, it will be much easier for researchers to isolate Pseudo-nitzschia viruses in the future.
Trung Phan – Biology (Molecular, Cellular, & Developmental)
Trung’s strong interest in reproductive biology and developmental genetics emerged during the summer of his freshman year when he began researching Drosophila fertilization under the guidance of Dr. Barbara Wakimoto. Confronted with an exciting and novel research question about the enigmatic proteins that regulate sperm activation, Trung was inspired to investigate the molecular events that facilitate sperm development and function. His current project focuses on the characterization of an interesting protein that plays a role in acrosome biogenesis in Drosophila and has a complex evolutionary origin. With the generous support of the Levinson Emerging Scholars Program, Trung hopes to take his project to completion and share his findings with the scientific community to contribute to our understanding of species reproduction. Trung’s involvement with undergraduate research has enriched his knowledge of biology and helped him develop habits of independent learning and critical thinking that will further his growth as a scientist. After graduating, Trung intends to pursue a career in medicine that will integrate his training as a cellular and molecular biologist.
Mentor: Dr. Barbara Wakimoto, Biology
Project Title: Analyzing the Critical Role of Pskl, a Sperm Membrane Protein, in Drosophila Fertilization
Abstract: The process of sexual reproduction in plants and animals is both a fascinating and mysterious property of life. During fertilization, the sperm delivers the paternal genetic material to the egg to begin formation of an embryo. However, the mechanisms that regulate sperm and egg interactions, such as gamete membrane fusion, are not well understood at the molecular level for any organism. The goals of this project are to identify and characterize the proteins that mediate sperm and egg interactions in Drosophila, an ideal model organism to study fertilization due to its rapid reproduction, short generation times, and genetic traits that are easy to observe. In Drosophila, an uncharacterized protein called Pop-sickle (Pskl) is of particular interest because pskl mutants are male sterile, despite having motile sperm. Additionally, Pskl has a structural region similar to GCS1, a sperm-specific protein required for sexual reproduction in flowering plants, malaria parasites, and alga. To better understand Pskl’s function in fertilization, we propose a two-fold approach to identify the protein’s site of action and its functional domains. The first experiment will subcellularly localize Pskl in developing spermatids by expressing a version of the protein marked with a fluorescent tag. In the second experiment, we will generate internal pskl deletions in the GCS1-like region and another region similar to a family of protist proteins. This will enable us to determine if these domains are necessary for normal Pskl function. Taken together, the results from this study will help clarify the molecular mechanisms required for sexual reproduction and ultimately contribute to the development of reproductive therapeutics that will treat male sterility. Furthermore, studying Pskl’s role in sperm-egg interactions might provide insight into mechanisms of fertilization that are evolutionarily conserved across diverse species.
Margaux Pinney – Biochemistry, Chemistry
Margaux is a senior in Biochemistry (BS), Chemistry (BS) and Mathematics (minor) with Departmental Honors in Chemistry and Biochemistry. After transferring to UW from Green River Community College, Margaux began doing research in the lab of Professor Jim Mayer. In the Mayer Group, she investigated the potential for proton-coupled electron transfer at synthetic iron-sulfer clusters, before moving on to her current, independent project. She now investigates the reversibility of Compound I formation in horseradish peroxidase. Compound I is also an intermediate in the catalytic cycle of cytochrome P450s. Since approximately 70% of xenobiotics, such as drugs or chemicals from the environment that enter the body, are oxidized by P450s, this research has pharmaceutical and toxicological implications. This research could also be applied to synthetic processes, due to the unique mechanism of oxidation. Based on her experience with undergraduate research at the University of Washington, Margaux will be pursuing her PhD. in biochemistry after graduation. Margaux is also involved with several groups on campus, such as the Tolo Chapter of Moratar Board, a senior honors society, as well as the Undergraduate Research Leaders, and is particularly interested in getting students, particularly women, involved in undergraduate research.
Mentor: Jim Mayer, Chemistry
Project Title: Reversibility of Compound I Formation by Horseradish Peroxidase
Abstract: Horseradish peroxidase (HRP) is part of a family of heme-containing metalloenzymes that reduce the O-O bond of peroxides while oxidizing a wide variety of substrates; in the case of HRP, hydrogen peroxide is reduced to water. In the presence of an oxidant and the absence of a substrate to oxidize, hydrogen peroxide coordinates to the iron cofactor of HRP, forming a ferric-hydroperoxide intermediate known as Compound 0, and subsequent O-O bond cleavage forms water and a very oxidizing ferryl-oxo porphyrin radical cation intermediate, known as Compound I. Compound I is of particular interest because it is also formed by cytochrome P450s, a family of enzymes that react with almost all foreign substances entering the body, including drugs and other chemicals in the environment. HRP is an excellent enzyme to test this reversibility because, unlike P450s, it is extremely robust and easy to work with. The goal of this project is to probe the potential reversibility of Compound I formation, a step traditionally thought to be irreversible. A key experiment will react HRP with excess unlabeled H2O2 in 18O-labeled water, and determine whether mixed-labeled H2O2 is created, which indicates that the step that forms Compound I is reversible. The enzyme will be removed by protein filtration and the existence of mixed-labeled H2O2 will be probed by adding a water soluble phosphine to the filtrate, which will readily react with excess H2O2 and be oxidized. 31P NMR spectroscopy will be used to determine whether the phosphine oxide is labeled because the NMR shifts of 16O-phosphine oxide and 18O-phosphine oxide are distinct. If this reaction proves to be reversible, this knowledge could then be used to describe cytochrome P450s. This research would be immensely important to pharmaceutical and toxicological research, as well as synthetic processes.
Denis Smirnov- Biochemistry, Neurobiology
Denis Smirnov is a senior at the University of Washington majoring in Biochemistry and Neurobiology. Having grown up in Russia, he has spent the last 10 years of his life in Seattle, attending Juanita High School in Kirkland before coming to UW. He is currently working in the laboratory of John Neumaier, MD., PhD. in the Department of Psychiatry and Behavioral Sciences, on a project aimed to understand the neural circuitry underlying addiction and relapse to drugs of abuse. He recently presented this research at the Society for Neuroscience conference in San Diego, and was an author of a recent publication in the Journal of Clinical Investigation, detailing a novel microPET imagine technique to map whole brain function in both anesthetized and awake, freely-moving animals in a highly sensitive manner. Involved in research for over 3 years across three different labs ranging to biochemistry, to chemistry, to neurobiology, Denis has worked extensively to prepare himself for a career in academic medicine. Upon graduating in the Spring of 2014, he plans to pursue an MD at a research oriented medical school, with the hope of one day becoming a neurologist or neurosurgeon.
Mentor: John Neumaier, Psychiatry
Project Title: The Role of the Lateral Habenula and the Rostromedial Tegmental Nucleus in Cocaine Addiction
Abstract: An important problem in the treatment of cocaine addiction is the vulnerability of previously addicted individuals to relapse to cocaine use months or even years after abstinence. The lateral habenula (LHb), part of the habenular complex in the dorsal diencephalon, and the rostromedial tegmental nucleus (RMTg), a recently identified nucleus in the reticular formation, are important regulators of the midbrain dopaminergic systems that are known to be involved in cocaine taking and relapse behaviors. However, very little is known about the precise role of these nuclei in cocaine reinforced behaviors. Here, I initially characterize the anatomical location of the RMTg using expression of the transcription factor cFos, as a marker of neuronal activation in response to cocaine. Next, we utilize the Designer Receptor Activated Exclusively by Designer Drug (DREADD) technology, to investigate the role of modulating the activity of the LHb on cocaine-self administration in rats. We demonstrate that DREADD-mediated transient silencing of the LHb through the activation of a Gi-coupled signaling pathway increases cocaine self-administration, while transient stimulation through the activation of the Gq-coupled signaling pathway decreases self-administration on a progressive ratio schedule, suggesting a reciprocal role between LHb and VTA activity. We further show that inactivation of the LHb to VTA projections has no effect on cocaine self-administration. Given this, we propose to investigate the indirect LHb projections to the VTA through the RMTg using our newly developed dual-virus strategy to specifically target the LHb to RMTg projection for DREADD-mediated modulation on self-administration and reinstatement.
Hunter Bennett – Bioengineering
Hunter Bennett is a junior in the Department of Bioengineering. Upon arriving at UW in Fall 2010, he was amazed at the work being done across campus to create novel systems for disease treatment and prevention and sought to get involved as a way to apply what he had learned in high school and to make a positive change in the medical field. This interest in research led him to the lab of Dr. Kim Woodrow in the Department of Bioengineering where it grew into a passion. In the Woodrow Lab, Hunter investigates the potential of cell-seeded hydrogel systems to induce mucosal and systemic immunity to HIV. He is also involved in a project investigating the chemokines responsible for dendritic cell recruitment during acute HIV-1 infection at the vaginal mucosa. Over last summer, Hunter participated in the Amgen Scholars Program at UCLA where he worked on social signaling in African Trypanosomes under Dr. Kent Hill in the Department of Microbiology, Immunology and Molecular genetics. After graduation Hunter plans to follow his passion for research by pursuing a PhD. Outside of lab, Hunter enjoys running, playing basketball and reading.
Mentor: Kim Woodrow, Bioengineering
Project Title: Encapsulation of Cell Based Therapeutics for the Prevention of HIV Infection
Abstract: The Human Immunodeficiency Virus (HIV) is a cause of widespread global suffering infects 2.7 million new patients each year. No cure exists for HIV and many experts believe that the disease will only be eradicated through the development of an effective vaccine. Virus-like particle (VLP) based vaccines capable of lowering the rates of HIV infection are promising but have been limited in application by their short half life in vivo and requirement of significant medical infrastructure. The implantation of cell lines producing HIV VLPs into patients represents a potentially cost-effective strategy for providing long-term protection from the HIV virus. Different alginate-based microcapsules will be made using electrostatic droplet generation. Particles will be examined for stability in conditions modeling that of common implantation sites, with promising microcapsules proceeding to cell viability studies. Results from cell viability studies will be used to select microcapsule formulations capable of sustaining healthy cell populations for long periods of time in vivo. 293T cells transfected with either the HIV gag gene or the HIV env gene will then be seeded in the microcapsules and assessed for its ability to elicit an anti-HIV antibody response and lower rates of infection in both cell and animal models. The goal of this research is to produce a cell-seeded alginate based microcapsule system capable of lowering rates of HIV transmission over extended periods of time.
Eric Do – Bioengineering
Now immersed in my fourth year as a senior in the Bioengineering department, with a capstone design project underway, I am able to reflect on my research experiences. Coming into college, I had never anticipated reaching the level of research involvement I have been able to obtain during my undergraduate years. In addition to my capstone work, I have been fortunate enough to have taken part in a diverse set of research experiences through summer programs at the Wake Forest Institute for Regenerative Medicine and the Johns Hopkins Institute for NanoBioTechnology (NSF REU). Nevertheless, I developed an interest in actively engaging in research with applications toward global health and medicine, which allowed me to find footing with the Woodrow Lab for my senior capstone project. Since junior year, I have been working to develop nanoparticles to achieve combination delivery of antiretroviral drugs with different mechanisms of action. My project aims to gain insight in identifying unique drug-drug interactions for HIV prevention. Altogether, I have come to appreciate not only my interdisciplinary research background but also its gradual impact in shaping me into the student I am today. I am extremely thankful for the generous support provided by the Levinson Emerging Scholars program as it will further motivate me to focus on my research and pursue my interest in medicine and biomedical research.
Mentor: Kim Woodrow, Bioengineering
Project Title: Developing nanoparticle-based antiretroviral topical microbicides for HIV prevention
Abstract: According to the UNAIDS 2010 Global Report, roughly 33.4 million people were living with HIV in 2008, with two thirds of them being in Sub-Saharan Africa. Females are disproportionately affected by the HIV epidemic and women-initiated prevention methods are lacking. To address this, we propose nanoparticle-based combination antiretroviral microbicides as an effective topical strategy for the prevention of HIV infection. Currently, most candidate-microbicides consist mostly of gels, which have demonstrated poor efficacy in clinical trials. Studies have supported the successful impact of highly active antiretroviral therapy (HAART) as a standard of care for HIV/AIDS affected individuals, which has motivated the investigation of the topical delivery of combination antiretroviral drugs. The proposed work has the potential to address the delivery challenges brought upon by the diverse classes of ARV drugs. The primary appeal for this approach lies in the combination delivery of drugs with different properties and mechanisms of actions to minimize chances of resistance and improve efficacy. In Phase 1, design of the nanoparticles as well as drug encapsulation and release kinetics will be assessed. In Phase 2, bioactivity and combination studies (Chou and Talalay method) will be performed to identify synergistic drug combinations and favorable drug-drug interactions. In Phase 3, tissue biodistribution and penetration of the nanoparticle microbicides will be performed. The research plan is designed to develop and evaluate nanoparticle microbicides as drug delivery systems for HIV prevention. Successful outcomes of this endeavor could have profound implications on microbicide research and a potentially viable female-controlled prevention method for HIV.
Nile Graddis – Psychology
Nile Graddis is currently a senior majoring in Psychology. He became involved in research as a sophomore working in Dr. Mizumori’s lab. Nile is interested in examining the neurobiology of learning and memory because of the critical contributions that learning makes to human as well as animal behavior. He hopes that by elucidating some of the basic mechanisms of learning, we might be better able to help those with learning disabilities or addictions. In Dr. Mizumori’s lab Nile has used electrophysiological and behavioral methods to explore the role of burst dopamine release on hippocampal place cell activity and local field potentials. His current research focuses on the influence of striatal projection neurons to modulation of learning rate. He seeks to use pharmacological, behavioral, and electrophysiological techniques to better understand the contributions that the neurons of distinct striatal projection pathways make to the activity of midbrain dopamine neurons and to learning. In his spare time, Nile enjoys reading and spending time with his friends.
Mentor: Sheri Mizumori, Psychology
Project Title: Understanding the roles of striatal projection neurons in modulating prediction error signaling
Abstract: How do we learn from our mistakes? One interesting possibility is that dopamine neurons in the midbrain compute a prediction error signal, which reflects the difference between expected and received rewards. This signal, which has been observed at the level of individual neurons, can then inform learning and future behavior. Despite the potential importance of this signal, the brain systems that modulate it are not well understood. Neurons of the ventral striatum project reciprocally to midbrain dopamine neurons, and may thus be involved in modulating the prediction error signal. These neurons project along two pathways, the direct striatonigral pathway and the indirect striatopallidal pathway, which have historically been difficult to manipulate separately. Recent advances in optogenetics and pharmacogenetics have made study of the pathways possible, leading to findings that these two populations of neurons antagonistically modulate learning. I propose to extend these behavioral findings by using electrophysiological and pharmacogenetic techniques in concert to investigate the roles that these distinct pathways play in modulating prediction error signaling. I will assess reward prediction signaling in midbrain dopamine neurons as rats learn on a two-choice operant maze task. I will use designer receptors exclusively activated by designer drugs to selectively inactivate neurons of the two striatal populations as rats perform this task. This will allow me to assess the roles played by neurons of these populations in modulating prediction error signaling. I hypothesize that inactivating one population of striatial neurons (striatonigral) will inhibit learning and impede the development of prediction error signaling while inactivating the other (striatopallidal) will have opposite effects. This work will provide valuable insight into the neural processes through which we learn from our mistakes. Such knowledge may allow us to provide better help to people suffering from addictive or compulsive behavioral disorders.
Danee Hidano – Bioengineering
Danee Hidano is currently a senior majoring in Bioengineering. She originally discovered her passion for research during her senior year of high school while interning at ZymoGenetics. As a freshman at UW, she joined Professor Dan Ratner’s lab. The Ratner lab specifically focuses on the role of carbohydrates in the body and how they can be utilized to develop new drug delivery mechanisms. She was particularly drawn to biomedical research for its direct clinical relevance. In the lab, Danee synthesizes sugar-based polymers that are designed to carry toxic drugs into specific cells via active-targeting. Danee also works at PhaseRx, a pharmaceutical company in Seattle, as a chemistry lab assistant. After graduation, Danee intends to pursue a career in medicine with a continued emphasis in biomedical research. In her spare time, Danee enjoys playing soccer, drinking coffee, and hanging out with friends.
Mentor: Daniel Ratner, Bioengineering
Project Title: Using Carbohydrate-Targeting Copolymers for Drug Delivery
Abstract: Carbohydrate complexes, such as glycolipids and glycoproteins, serve as cellular markers and receptors universally found on the outer membranes of mammalian cells. These glycoconjugates distinguish different types of cells from one another and enable cellular recognition and adhesion. Both the immune system and foreign pathogens rely on these glycoconjugates to bind and enter host cells. For viruses and bacteria, adhesion to receptors is the first step in infection. Carbohydrates are highly diverse and are each able to bind to unique receptors. By mimicking nature, chemists use carbohydrates to bind and enter specific cells for drug delivery.
Active drug targeting is highly advantageous because the ability to deliver drugs exclusively to specific cells or organs reduces increases efficacy of the drug and decreases toxicity. In my current research, I am designing a drug carrier that takes advantage of these specific carbohydrate-receptor interactions to deliver small molecules into cells. Currently, I have successfully synthesized and characterized the carbohydrate monomers responsible for targeting. Next, I will synthesize the glycopolymer to function as the drug carrier. The glycopolymer is composed of three main components: (1) carbohydrate, (2) pyridal-disulfide methacrylamide (PDSMA), and (3) hydroxyl-ethyl methacryamide (HPMA).
Firstly, the carbohydrate monomers enable specific binding interactions that are leveraged to exclusively deliver therapeutics to intended cells. Secondly, the PDSMA monomers allow for versatile conjugation of any thiolated small molecule – including Doxorubicin (for chemotherapy treatment), peptides (for vaccines), or genetic material (for gene therapy) – through a disulfide exchange. Lastly, HPMA gives the copolymer biocompatible characteristics, such that it is more soluble and less immunogenic in vivo. Overall, due to the natural complexity and diversity of carbohydrates, the carbohydrate-based copolymer construct has promising potential as an active targeting drug carrier to both reduce toxicity and increase in drug efficacy.
Ben Horst – Biochemistry, Chemistry
Ben is currently a senior and will graduate in the spring with degrees in Chemistry (BS, ACS certified), Biochemistry (BA), and Mathematics (minor) as well as College Honors and Departmental Honors in Chemistry and Biochemistry. He got his first research experience the summer after his freshman year in the lab of Professor Sarah Keller fabricating and analyzing model cellular membranes. With the Keller group he presented work at the Undergraduate Research Symposium, the Northwest ACS Undergraduate Symposium, and the 2012 National Biophysical Society Meeting. The time he spent in the Keller Lab propelled him to take the next step in his research career by joining the group of Professor James Mayer in studying inorganic chemistry, specifically reduction/oxidation and biomimetic inorganic chemistry, and nanoparticles. When Ben first joined the Mayer group, he undertook a project himself without a graduate student or postdoctoral mentor to study a specific type of reduction/oxidation mechanism called a Multiple-Site Concerted Proton Electron Transfer reaction in which a carbon hydrogen bond is cleaved by transferring the proton to a base and the electron to an oxidant. Now he is collaborating on a new project that combines TiO2 nanoparticles and Concerted Proton Electron Transfer to complete a non-trivial two electron, two proton transfer under relatively mild conditions.
When not in the lab, Ben enjoys TAing in the Chemistry department, running, hiking, sports, and music, playing snare drum in the University of Washington Drumline and singing bass in an a cappella choir on campus.
Mentor: James Mayer & Sarah Keller, Chemistry
Project Title: Model System for Multiple Site Concerted Proton Electron Transfer
Abstract: Reduction/oxidation reactions are crucial for energy transfer in a wide variety of applications such as water oxidation, water remediation, and biological processes. Proton Couple Electron Transfer (PCET) reactions are increasingly recognized as an important class of this type of reaction. As hinted by their name, these reactions involve the transfer of a proton and an electron from a substrate to other molecules. However, PCET reactions can be delineated further into Single Site PCET reactions, where a single reagent acts as both the electron and proton acceptor, and Multiple Site PCET reactions, where different molecules accept either the proton or the electron. This investigation focuses on these specific Multiple Site PCET reactions (MS-PCET) which are generally not well understood, specifically the breaking of a C-H bond. Using a model system consisting of an oxidant (FeIII(bpy)3-), a base (2,2′-bipyridine) and a substrate (9,10-dihydroanthracene), MS-PCET reactivity will be monitored in an attempt to understand the kinetics of the reaction. Different techniques are used to elucidate the progression of the reaction including UV/Visible and 1H NMR spectroscopy, and stopped-flow injection. The rate of reaction is dependent on each of the reaction components, as well as solvent, temperature, and the surrounding atmosphere. Kinetic analysis of the reaction will eliminate other proton electron transfer reactions and show that the Multiple Site PCET is the singular, plausible mechanism. These reactions will help to establish an understanding of MS-PCET reactions which are crucial to so many biological systems and new technologies such as fuel cells and solar energy.
Emily Hsieh – Biochemistry, Biology
Emily Hsieh was first exposed to the field of evolutionary biology the summer before entering the University of Washington and since then has been interested in utilizing the intricacies and wonders of Drosophila genetics to better understand one of Darwin’s “mysteries of mysteries” – the formation of new species. Under the direction of her mentors Drs. Harmit Malik and Nitin Phadnis, she has been involved in various projects exploring her research interests of genetic conflict and speciation in the context of Drosophila. With the generous support of the Levinson Emerging Scholars Program, Emily hopes to continue her research in understanding the genetic basis of speciation in Drosophila and contribute to the understanding of the origin of species. The culmination of Emily’s undergraduate experience as a MCD biology and biochemistry student and as a Malik lab undergraduate researcher has strengthened her desire to pursue a PhD in biology. Emily enjoys spending her spare time mentoring students through the UW Dream Project and would also like to integrate educational outreach and science into her future career.
Mentors: Harmit Malik & Nitin Phadnis, Fred Hutchinson Cancer Research Center
Project Title: Disentangling the Role of Dosage Compensation in F1 Hybrid Incompatibility
Abstract: The process for how species form in nature remains a complex and fascinating puzzle. One approach to solving this mystery is by identifying genes involved in F1 hybrid incompatibilities, characteristics that typify an F1 hybrid offspring. Of particular interest is the dosage compensation complex, also known as the male-specific lethal (MSL) complex in Drosophila, since it contains MSL proteins that show strong signatures of rapid evolution, but not in all closely related species. Much controversy surrounds the idea of the MSL complex playing a role in F1 hybrid incompatibility, and here, I use a three part analysis to approach this question. Drosophila melanogaster and simulans are fitting models to study F1 hybrid incompatibilities as they are recently diverged species that produce inviable F1 hybrid males. The first experiment will test to see if the MSL complex is functional in F1 hybrid males through the usage of a male-killing bacterium Spiroplasma poulsonii, a detector of functional MSL complexes. The second assay will examine if the MSL complex is aberrantly turned on in attached X F1 hybrid females as a proxy to study MSL complex function in F1 hybrid males. Finally, the third experiment determines the functional divergence of D. melanogaster and D. simulans MSL complex proteins. Within the MSL complex, either MSL1 or MSL2 are necessary for male viability, so by creating transgenic flies with different combinations of D. melanogaster and D. simulans msl1 and msl2, I will be able to use an interspecies complementation test to identify if divergence of these two genes has led to F1 hybrid incompatibility. This inclusive set of experiments offer multiple approaches to uncover a possible role of dosage compensation in the mechanism of speciation in Drosophila.
Joanne Hsu – Neurobiology
Growing up in the forests of Battle Ground, WA, Joanne frequently encountered flora and fauna of diverse phenotypes as she explored the woody backyard, which was what first inspired her passion for the biological sciences. Her interest in exploring biological processes and function on level of proteins inspired her to conduct proteomics research with Dr. Judit Villen in the Department of Genome Sciences, where she studies the evolution of phosphoregulation across yeast species using proteomic techniques and mass spectrometry. The goal of this project is study the conservation of phosphorylation sites across representative yeast species from different phylogenetic lineages, to identify specific orthologs that regulate key cellular functions and also better understand the evolution of phenotypic diversity.
Joanne is very grateful for the support from the Levinson scholarship on her research.
Mentor: Judit Villen, Genome Sciences
Project Title: Elucidating the Conservation of Phosphorylation Patterns Across Yeast Species with Phosphoproteomics
Abstract: The reversible phosphorylation of proteins mediates a wide range of biological processes that range from signal transduction cascades to regulation of protein abundance. However, little is known about the mechanisms and evolution of phosphorylation networks. Despite the extraordinary advances in genome sequencing of many yeast species, evolutionary studies on the phosphoproteome of yeast species have been limited to the experimental analysis of phosphorylation in one species and computational analysis of the conservation of phosphor-acceptor residues with other species. To properly study evolutionary conservation across yeast proteomes, we are utilizing mass spectrometry to study and compare the phosphoproteome of over 15 species of yeast, including species representative from each clade on the yeast phylogeny. Most of these species have not been studied before by proteomics. This high-throughput phosphoproteomic study on the yeast species will contribute to the construction of phosphoproteome datasets, which can be exploited for comparative analysis of phosphorylation between yeast species. In this phosphoproteomic study, I will first analyze the reproducibility of the sample preparation techniques and data acquisition methodologies, which are key factors in the ability to distinguish true differences between samples. After developing an optimally reproducible methodology, I will construct growth curves for all the yeast species, in order to standardize an optimal optical density for the yeast cultures. Next, I will analyze the phosphoproteome of the yeast species using the optimized phosphoproteomic methodology, in order to construct the phosphoproteome datasets. To supplement the datasets, I will also analyze the protein abundances in each of the species. The relative overlap between the phosphoproteome datasets and the comparison of protein abundances between the yeast species will shine light on the evolutionary and functional relevance of phosphorylation in regulating protein concentration and mediating cellular signaling pathways.
Tinny Liang – Bioengineering
Initially pre-med focused, Tinny Liang joined the joint lab of Professors Paul Yager and Elain Fu during her freshman year; joining the lab has since opened the doors to biomedical research as a career. Currently a senior In the Department of Bioengineering, Tinny was drawn to technology’s ability to expand access to health care. Her interest and motivation to pursue research on paper-diagnostics for low resource settings is motivated by the fact that while there are cures for many infectious diseases (e.g. malaria, dengue) millions of people in developing countries still die from them. Millions of lives can be saved, and quality of life can be improved if given the tools for accurate diagnosis. With her mentor Professor Elain Fu, she has designed a novel paper-based malarial diagnostic test with improved sensitivity for the detection of infectious diseases in low resource settings. Tinny is currently working on incorporating a new paper-based tool to control reagent transport through this novel test for further improved sensitivity and improved test usability. She plans to continue her passion for biomedical research by pursuing an MD/PhD. Outside of the lab, Tinny is an active Biomedical Engineering Society Officer, volunteers at the Anatomic Pathology department at the University of Washington Medical Center, and leads several Bioengineering outreach events for high school students. She also enjoys playing badminton and cooking with friends.
Mentor: Elain Fu, Bioengineering
Project Title: Development of a Prototype Paper-based Malarial Diagnostic Device
Abstract: Millions of people in developing countries die from infectious diseases (e.g. malaria and dengue), yet many of these deaths can be prevented if giving the tools for accurate diagnosis. However, current diagnostic capabilities with the required clinical sensitivity are confined to laboratory settings due to cost, electrical, and personnel requirements. The current method for diagnosis of infectious diseases in low resource settings is lateral flow tests (LFTs), which have the appropriate usability but confined to single chemical step lack the required sensitivity. Thus there is a medical need for diagnostic tools with the required level of clinical sensitivity and usability for use in low resource settings. I will design a novel device capable of controlling fluid steps within a two dimensional paper networks (2DPN), which enables more sophisticated chemical processes for diagnosis in low resource settings for improved sensitivity and usability. The novel device will utilize commercial enhancement solutions for signal amplification via a metal catalytic reaction to increase sensitivity. I will determine the optimal set of reagents and reagent volumes that yields the highest sensitivity. A new 2DPN assay device will be designed to accommodate the reagent set and volumes, where sequential delivery of reagents is achieved through manipulation of paper geometry. I will then incorporate a fluidic on-switch into the paper network to improve usability (i.e. by reducing the size of the device and the time to read out).
Kien-Thiet Nguyen – Neurobiology
It was during his time at a high school internship at Seattle Biomedical Research Institute that Kien-Thiet Nguyen first became exposed to research culture. Since his first ELISA, he has eagerly pursued research opportunities. As an undergraduate intern in the lab of Theodore White, he researched the import and transcriptional effects of certain classes of antifungals. During his sophomore year, he joined Gwenn Garden’s lab researching the neurodegenerative disease, spinocerebellar ataxia type 7 (SCA7). His earlier research has shown in SCA7 there are changes in climbing fiber inputs to Purkinje cells, a vulnerable neuronal cell type in the cerebellum. His current research involves analysis of microRNA expression in microdissected Purkinje cells in SCA7 and nontransgenic mice. By utilizing basic bioinformatics techniques, Kien-Thiet hopes to identify and validate microRNA and their mRNA targets that are most differentially affected in SCA7. Kien-Thiet plans on pursuing a Ph.D. in neuroscience, with the goal of a career in translational research focusing on neurodegenerative diseases.
Mentor: Gwenn Garden, Neurology
Project Title: Analysis of Altered miRNA Expression in a Transgenic Mouse Model of SCA7
Abstract: Spinocerebellar ataxia type 7 (SCA7) belongs to a family of neurodegenerative diseases. It is characterized by degeneration of the cerebellum and brainstem. The disease is caused by an expanded polyglutamine tract in ataxin 7. This type of polyglutamine mutation is a common feature in many neurodegenerative diseases. Other neurodegenerative disease including those involving polyglutamine expansions demonstrate altered microRNA (miRNA) expression. Given the supporting evidence that miRNA are differentially expressed in other polyglutamine diseases, I seek to determine the role of miRNAs in SCA7. My proposed research will analyze altered miRNA expression in Purkinje cell neurons, a selectively vulnerable neuronal population that degenerate in SCA7. I will first identify miRNAs that are upregulated or downregulated in Purkinje neurons from SCA7 mice. Next using predictive databases I will identify their potential mRNA targets. I will then test identified miRNAs in cell culture to see if they will inhibit expression of their predicted target. If expression is inhibited, I will then measure the level of mRNA and protein of the predicted target in transgenic mouse tissue. By identifying miRNAs that are differentially expressed in SCA7 mice and confirming their activity, we can build our understanding of the mechanisms of disease progression in SCA7.
Jacqueline Robinson-Hamm – Bioengineering
Jacqueline was forced to end her gymnastics career early due to a rare degenerative bone disease in her right elbow. However, investigations into the disease and lack of treatment inspired her to pursue bioengineering. Her passion lies in novel ways to treat disease. She joined Dr. Regnier’s Heart and Muscle Mechanics laboratory sophomore year, inspired by the ongoing work to address the loss of function post heart attack. The rich and supportive environment has helped her develop greatly as a scientist. Senior year she is collaborating with Dr. Marcinek’s Translational Center for Metabolic Imaging to investigate a novel gene therapy to treat loss of function in skeletal muscle. She plans to attend graduate school and earn her PhD in bioengineering. Following graduate school, she hopes to gain a faculty position at a top research institution and continue in meaningful research, as well as teach to help train the next generation of bioengineers.
Mentor: Michael Regnier, Bioengineering
Project Title: Performance characterization of cardiac and skeletal muscle with increased 2-deoxy-ATP
Abstract: Cardiovascular disease and skeletal muscle disease that result in loss of contractile function affect people around the world. Current heart disease therapies aid in slowing the progression of heart failure, but there are no treatments that restore healthy cardiac function short of transplant. Dr. Regnier’s laboratory is pursuing a novel treatment for heart disease that will prevent the progression of heart failure by restoring cardiac function to healthy levels. The laboratory has discovered that a nucleotide analog of ATP, 2-deoxy-ATP (dATP), which is produced in cardiomyocytes, greatly improves cardiac performance. The Regnier laboratory has studied the effect of increased dATP concentration in cardiomyocytes in both transgenic animals that overexpress the enzyme that catalyzes dATP formation, ribonucleotide reductase (R1R2), and in cells virally modified to have R1R2 overexpression. In both models, the therapeutic effect of increased dATP concentration was observed: cells with increased dATP concentration have an increased rate and magnitude of contraction, and an increased rate of relaxation. To further the study, I will be initiating collaboration with Dr. David Marcinek’s laboratory to explore the effects of dATP in skeletal muscle in transgenic mice. Twitch, tetanus, and fatigue protocols will be conducted on both in vivo and in vitro skeletal muscle from wild type and transgenic mice that overexpress R1R2. The combined findings from both laboratories will help complete the characterization of how increased dATP concentration affects muscle and whether upregulation of this nucleotide might be beneficial in treating skeletal muscle disease as well as cardiac disease.
Jeffrey Benca – Plant Biology
Spurred by a lifelong passion for prehistoric life, Jeff Benca’s research uses modern and fossil representatives of ancient plant lineages to study ecosystem dynamics and environmental changes in deep time. Joining the lab of paleobotanist Dr. Caroline Stromberg in the UW Department of Biology his sophomore year, Jeff began implementing extant plants from teaching and research collections he built at the UW Botany Greenhouse to study evolutionary trends in early vascular plants. With Dr. Stromberg, he studied morphological variation in modern clubmosses and later the extinct Devonian lycopsid genus Leclercqia across six continents and 12 million years, resulting in the description of a new species from Northern Washington State.
Now, Jeff is exploring whether leaf morphology in living lycopsids and ferns, plant groups that once dominated many of earth’s ecosystems ~360 million years ago, is influenced by climate. Conducting growth chamber experiments growing lycopsids and ferns under two temperature regimes he hopes to find out whether temperature can induce changes in leaf shape. If temperature does influence leaf physiognomy of these plants, it may be possible to calibrate fossil leaves of their ancestors as new tools for assessing paleotemperatures during the Late Paleozoic. Developing more accurate temperature baselines during this time period is particularly important as it could yield entirely new analogs to modern climate change. In the coming years, Jeff plans to pursue a PhD using living and fossil plants to better understand environmental changes associated with mass extinctions and climatic changes in the distant past while making paleobiology more accessable and hands-on for students and the general public through teaching and continued outreach.
Mentor: Caroline Stromberg, Biology
Project Title: Climatic Influences on lycopsid and fern leaf physiognomy
Abstract: Understanding modern climate change hinges upon our ability to assess past climates. While relatively few analogs to modern climate change are represented in recent geological history, the Paleozoic era may offer more. Investigating Paleozoic climates could allow for study of long-term impacts of dramatic environmental transitions on terrestrial ecosystems. But exploring climate shifts in the distant past will require the expansion of existing techniques. Several methods use fossil leaf morphology to infer past climatic conditions. One such approach called Leaf Margin Analysis (LMA) uses leaf margin toothiness to infer past mean annual temperature. This approach has proven successful in using modern floras to estimate regional climates but can only assess past climates as far back as 120 million years ago (Ma) since it currently only utilizes leaves of flowering plants. However, other more ancient groups of vascular plants have evolved leaves with toothed margins as well. With toothed leaves and a fossil record exceeding 350 Ma, lycopsids (clubmosses) and ferns have potential to extend LMA back to the Late Paleozoic. To determine whether climate (in particular, temperature) influences leaf morphology in living representatives of these lineages, we are growing two species of lycopsid and two species of fern under two temperature regimes; 15°C and 25°C. If tooth number or size increases under cooler temperatures, fossil relatives of these ancient vascular plant lineages could potentially be implemented for study on climate changes long-preceding the age of flowering plants.
Ben Dulken – Bioengineering
Ben Dulken is currently a senior in the Bioengineering department. He got his first exposure to biomedical research as a lab assistant in the Kaeberlein Lab (UW Patholgy) during his freshman year. He was drawn to research by the opportunity to apply what he had been learning in his classes to achieve clinically relevant findings which could improve the quality of life for suffering individuals. He spent about a year in the Kaeberlein Lab investigating the genetic mechanisms of aging in yeast. Subsequently, Ben moved to the lab of Prof. Suzie Pun in the Department of Bioengineering to investigate novel drug delivery materials. While in the Pun Lab, Ben has been involved with several projects including the development of a micelle delivery system for solid tumor imaging agents and chemotherapeutics, and his current project, the investigation of a novel drug loaded hydrogel to provide controlled delivery of an ototherapeutic agent to the inner ear over an extended period of time. Throughout his undergraduate career he has participated in several research-oriented programs including the Amgen Scholars Program and the DAAD Research Internships in Science and Engineering. He plans to continue to pursue his passion for biomedical research by pursuing an MD/PhD. When he is not in the lab, Ben enjoys cycling, hiking, and playing the piano.
Mentor: Suzie Pun, Bioengineering
Project Title: Novel hydrogel for the delivery of cochlear therapeutics using complexation of ß-cyclodextrin conjugated PEO-PHB-PEO triblock copolymers and adamantane conjugated multi-arm PEGs.
Abstract: The loss of the hair cells of the cochlea of the inner ear can result in permanent hearing loss. Recently, the Rubel lab (UW Otolaryngology) has identified a molecule which can prevent hair cell death induced by the antibiotic neomycin, however, they have had difficulty delivering PROTO1 to the inner ear. This project involves the design, formulation, and characterization of a novel drug loaded hydrogel for delivery of PROTO1 to the inner ear. The drug loaded hydrogel will be applied at the round window membrane of the cochlea via surgical insertion. Over an extended period of approximately three to four weeks the drug contained in the hydrogel will be released and diffuse through the round window membrane into the fluid paths of the cochlea, where it is therapeutically active. The design will use modified PEO-PHB-PEO triblock polymer which will be cross linked by the interactions of adamantane and ß-cyclodextrin. The hydrogels will be composed of a mixture of ß-cyclodextrin conjugated triblock copolymers and adamantane conjugated multi-arm PEG. When these two polymers types are mixed, inclusion complexes between the adamantane and ß-cyclodextrin moieties will cross link the polymers and induce the formation of a supramolecular hydrogel. This work builds on previous work which has demonstrated the formation of hydrogels when the PEO-PHB-PEO triblock copolymer is cross linked with a-cyclodextrin This design is superior to its predecessor in that it could potentially allow for hydrogel formulation at lower polymer concentrations, and could potentially increase the stability of the hydrogel, sustaining drug release over a longer period of time. Hydrogel preparation parameters will be optimized by investigation of the thermosensitive, viscoelastic, and drug release properties of the hydrogel. The in vivo therapeutic efficacy of the drug loaded hydrogel will be measured in a rat or guinea pig model.
Molly Gasperini – Biochemistry and Chemistry
Both biology and issues of mental health have interested Molly since she was in high school. For the past two years, she has been able to work in both of these fields as she investigates a mutation in the DNA of a patient with schizophrenia. She has pursued this research under the mentorship of Dr. Mary-Claire King, in the departments of Medical Genetics and Genome Sciences, and Caitlin Rippey, a graduate student in the UW’s Medical Scientist Training MD/PhD Program. With the support of the Levinson Scholarship, Molly hopes to complete her analysis of this mutation and contribute to the understanding of the biological mechanisms of schizophrenia. This research experience, combined with her biology major and experience in activism for mental health awareness, has inspired her to pursue graduate school and a career in neurogenetics research.
Mentor: Mary-Claire King, Genome Sciences and Medicine
Project Title: Biological characterization of a genetic mutation implicated in schizophrenia
Abstract: Schizophrenia is a devastating neurodevelopmental disorder whose genetic influences continue to be elusive. Rare, gene-disrupting genomic deletions and duplications – called copy number variants (CNVs) – have been implicated in schizophrenia; however, much remains to be understood about which genes are causative, as well as the cellular mechanisms involved. Biological follow up on individual CNVs will give insight to the origin of schizophrenia. We focused on one that duplicates the 5′ ends of two genes that lie head-to-head on chromosome 11q22: DCUN1D5, a previously uncharacterized gene predicted to be involved in cullin neddylation of ubiquitin ligase complexes, and DYNC2H1, a dynein active in cilia. Both are expressed in brain and are plausible candidate genes for schizophrenia. Using RNAseq, we detected novel DCUN1D5 transcripts that we predict will result in truncated DCUN1D5 protein in the patient’s cells. In order to understand the function of DCUN1D5, we will determine which of seven possible cullin binding partners it interacts with using an in vitro neddylation assay. We will then test the conformational stability of truncated DCUN1D5 by Western blot in the patient’s cells and transfected cell lines. We will then be able to compare the function of the full length DCUN1D5 with the aberrant DCUN1D5 present in the patient. Investigation of these aberrant proteins may shed light on pathways that contribute to schizophrenia, potentially guiding the search for new candidate genes and the development of novel treatment strategies.
Teague Henry – Psychology
Teague Henry is interested in the methodology currently used to study psychology phenomena, specifically methods used to study social networks from a psychology perspective. After joining Kevin King’s lab during his sophomore year, he has been involved in a variety of projects investigating the role of impulsivity on substance use. The project funded by the Levinson will investigate the role of peers on individuals substance use. Currently, Teague is a senior working towards a major in psychology, with minors in mathematics and philosophy. He hopes to pursue a graduate degree in quantitative psychology, and continue to research and develop analytical techniques to investigate more complex problems in psychology.
Mentor: Kevin King, Psychology
Project Title: Context and Peer Influence on Adolescent Substance Use
Abstract: Adolescent substance use is a significant public health issue in America. Research has established that one of the best predictors of adolescent substance use is peer substance use. One of the processes that lead to this similarity in behavior is peer influence. Previous research has established that several factors, such as self-regulation, moderate an individual’s susceptibility to peer influence. However, little research has been done as to the effect of peer network characteristics and contextual characteristics on susceptibility to peer influence. The proposed study will investigate the effects of self-regulation alongside with peer network characteristics and contextual variables on susceptibility to peer influence. This study will use the Add Health dataset, a nationally representative longitudinal survey of adolescents. The data will be analyzed in a multi-level framework to simultaneously determine the effect of individual characteristics, peer network characteristics and contextual characteristics. Findings of this analysis will provide insight about the role of both environmental context and social context in determining an individual’s susceptibility to peer influence in regard to substance use.
Marvin Nayan – Biochemistry and Neurobiology
Since his first year as an undergraduate, Marvin Nayan has been engaged in neurobiology research at the Parrish Laboratory, where he investigates the genetic and molecular mechanisms responsible in regulating dendrite branching. Due to the importance of dendrite patterning to nervous system function, dendrite abnormalities have been linked to many neurological diseases. Marvin’s current research focuses on identifying and characterizing mutations that are defective in the development and maintenance of sensory neurons in fruit fly. Marvin hopes his research will lead to improvements in the diagnosis and treatment of many mental disorders. Thus far, Marvin’s research has guided him to be recognized as a Mary Gates Research Scholar, EOP Scholar, and EIP Presidential Scholar. With the generous support of the Levinson Emerging Scholars Program, Marvin intends to continue neurobiology research in graduate school and plans to pursue a career in academia.
Mentor: Jay Parrish, Biology
Project Title: Characterizing the Metabolic State of Cancer and Embryonic Stem Cells
Abstract: Dendrites are branched projections of a neuron that chiefly function as information receivers, conducting stimuli from adjacent neurons or the external environment and relaying those synapses throughout the body of an organism. This elaborate, yet efficient, transfer of information from neuron to neuron is the hallmark of the nervous system. Therefore, any abnormality that alters how a neuron receives stimuli, such as the spatial arrangement of its dendritic arbor, can lead to defects in neuronal function. Given the importance of dendrite morphology to neuronal function, it is essential for neurons to maintain optimal coverage of their receptive field as the organism grows in size. However, the mechanisms underlying this phenomenon are poorly understood. We propose a genetic screen to identify genes that regulate maintenance of dendrite coverage. Our aim is to perform functional gene analysis and identify extrinsic regulators of dendrite maintenance. To this end, we will use a transgenic line of fruit flies bearing membrane-bound fluorescent proteins to visualize dendrites of dendritic arborization neurons in the peripheral nervous system. Following chemical mutagenesis, we will use confocal microscopy to screen for mutations that are defective in dendrite maintenance. Subsequently, I will characterize the site of action of mutations of interest using mosaic analysis and finally will positively identify the gene affected by a given mutation by performing a genetic rescue via P-element-mediated transformation. Results from this project will lead to greater understanding of neuronal development, including potential implications to many neurological diseases.
Bennett Ng – Bioengineering & Computer Engineering
Having cultivated an interest in computer technology since childhood, Bennett Ng discovered a passion for bioengineering during his junior year of high school. As an intern at Seattle BioMed, he gained first-hand experience with infectious disease research, and found a humanitarian purpose to guide his interest in computing. These experiences led him to become a student in the UW Department of Bioengineering, where he quickly joined Herbert Sauro’s synthetic biology lab to continue pursuing student research. As a sophomore, Bennett conducted computational research to elucidate optimal design targets in biochemical networks. Now as a senior, he is synergizing his interdisciplinary interests to develop a low-cost, open-source chemostat device in the Sauro lab. The device could enable and accelerate evolutionary stability experiments which are essential to the advancement of synthetic biology. Bennett is a dual-major in Bioengineering and Computer Engineering. Outside of the lab, he is actively involved as an officer for the Biomedical Engineering Society and Bioengineers Without Borders. He plans to pursue graduate study and a career in biotechnology industry.
Mentor: Herbert Sauro, Bioengineering
Project Title: Design of a Modular, Integrated Growth and Measurement System for the Extended Characterization of Biological Parts
Abstract: A key issue in synthetic biology is the evolutionary robustness of synthetic circuits. Creation of robust circuits requires the development of design criteria to extend evolutionary timescales, and insight into the relative evolutionary fitness of different circuit designs. Experimentally, this research requires the use of multiple cell culture runs that are time-consuming and laborious. To accelerate this work, development of a high-throughput, automated, and parallel mini-chemostat and turbidostat device is proposed.
While the development of nutrient-replenishing chemostat devices dates back to 1950, and the usage of such devices is well-documented, even modern chemostats are not well-suited to evolutionary experiments. Current designs face significant issues of equipment fouling, specialized complexity, and prohibitive cost. Presently there is a lack of cost-effective options for highly parallel milliliter-scale chemostat devices which can be applied to problems in synthetic biology.
The proposed device will be small and modular, utilizing multiple standard petri dishes for parallel culture experiments. The design will feature integrated media refreshment and temperature control mechanisms. Visible and fluorescent direct-view, real-time imaging systems will be included. The device will be constructed of readily-available parts to maintain low cost. Parts will be modular such that used petri dishes can be easily removed, disposed of, and replaced. The design will be scalable such that numerous devices can be stacked or tiled for parallel experiments. An open-source software package and electronic microcontroller system will be developed to allow for automated real-time measurement and customization of growth and measurement parameters.
Eric Secrist – Biology and Physiology
Eric Secrist is a senior at UW who has always been intrigued by the nervous system, particularly the areas which are not fully understood. He began working in Dr. Chet Moritz’s spinal cord injury lab in the rehabilitation medicine department during his sophomore year in order to pursue this curiosity. With assistance from Dr. Moritz and Dr. Mike Kasten, Eric developed and is currently conducting a brain-computer-interface experiment which links dopamine releasing medial forebrain bundle stimulation with functional movements of an impaired limb. The hope is that this research will contribute to the development of novel therapies for people with partial spinal cord injuries to regain movement in their arms and hands. After graduating this spring with a degree in Physiology and a minor in Bioethics and Humanities, Eric hopes to go to medical school and continue following his interest in neuroscience by becoming a neurologist.
Mentor: Chet Moritz, Rehabilitation Medicine and Physiology
Project Title: Dopamine Mediated Plasticity and Its Role in Recovery from Cervical Spinal Cord Injury
Abstract: Thanks to advances in safety equipment and emergency care, most spinal cord injuries that occur in people today are incomplete, leaving a portion of the spinal cord neural tissue intact. Further, recent research has shown that there is plasticity and axonal sprouting following injury, expanding the possibilities for rehabilitation from what was once considered a permanent and unrecoverable injury. Our goal is to enhance this process and work towards functional recovery. Dopamine, a powerful neurotransmitter involved in processes such as learning, memory and motivation, plays an integral role in brain plasticity. We are currently testing whether pairing dopamine release with functional movements can increase plasticity of the remaining active pathways and lead to increased functional recovery following an injury. We will test this by comparing the recovery of two groups of rats following partial cervical spinal cord contusion injuries in only one forelimb. Both groups of animals will receive dopamine-releasing electrical brain stimulation. For one group this stimulation will be synchronized with movements of the impaired limb. These rats will activate the stimulation by using their impaired forelimb to push a lever. The other group will receive stimulation at a time separate from desired forelimb movements, but will still have to push the lever in order to receive it. In both groups this stimulation will activate the medial forebrain bundle, a pathway in the brain strongly associated with dopaminergic pathways. The two groups will be compared on their ability to perform specific motor tasks with the injured forelimb. We hope to someday apply the knowledge we gain from this experiment to develop novel ways to promote nervous system recovery from injury by using dopaminergic pathways to reinforce neural plasticity. This may lead to therapies which allow people with incomplete spinal cord injuries to improve their fine motor skills.
Alexandra Taipale – Biochemistry
Alex Taipale came to the University of Washington from Colorado to study Biochemistry. She pursued her interest in research in Dr. Sarikaya’s Materials Science and Engineering lab and Dr. Yager’s Bioengineering lab. She finally found her passion for research when she began Human Immunodeficiency Virus Type 1 (HIV-1) research in Dr. Mullin’s Microbiology lab. During her time in the lab, she has worked on several different projects related to HIV-1 vaccine development. Her involvement in HIV research aroused her interest in HIV studies being performed with samples from female patients. Despite the fact that HIV-1 progresses differently in women than in men, there are far fewer HIV-1 studies conducted with female samples. Alex will spend her senior year studying HIV-1 evolutionary trends in female samples in order to make a comparison to the data generated in pre-existing male studies. After graduation, she hopes to continue her study of viral disease by pursuing a PhD in Microbiology or Biochemistry. Ultimately, Alex hopes to improve disease treatment and prevention through a career as a research scientist.
Mentor: James Mullins, Microbiology
Project Title: Sex Differences in Viral Evolutionary Trends Associated with the Progression of Human Immunodeficiency Virus Type 1 Infection
Abstract: The effect of viral evolution on the duration of latent Human Immunodeficiency Virus Type 1 (HIV-1) infection has been studied extensively in men. The asymptomatic latency period, after HIV-1 infection and before the onset of Acquired Immune Deficiency Syndrome (AIDS), is characterized by high viral variability. In many cases, a viral phenotype that utilizes CXCR4 and/or CCR5 receptors on target host cells to advance HIV-1 progression also emerges during this period. Despite known sex-dependent variation in the progression of HIV-1, the effect of viral evolution and CXCR4/CCR5 utilizing virus (X4 virus) prevalence on HIV-1 latency has not yet been studied in women. I will investigate trends in viral evolution in 9 women from seroconversion to the development of AIDS. I will then compare my results to previously studied male viral evolutionary trends. Over the course of three quarters, a total of 72 blood plasma samples, an average of 8 samples from each woman collected progressively during the course of infection, will be used to generate 25-30 HIV-1 sequences per time point. These sequences will then be evaluated through 1) viral divergence from a founder strain 2) viral population diversity and 3) emergence and prevalence of X4 viruses. I will then analyze the effect of viral evolutionary trends and X4 virus prevalence on the duration of HIV-1 infection before the onset of AIDS. Ultimately, a comparison between the sexes will be made. Furthering the scientific communities’ knowledge of sex-related HIV-1 infection variation could lead to more effective sex-specific treatment and vaccine development. The important biological question of whether sex can influence HIV-1’s evolutionary path will be addressed.
Michael Choi – Biochemistry and Chemistry
Michael Choi is very interested in biological and biochemical research especially with applications towards helping patients. Since his freshman year, he has been investigating embryonic stem cells and stem cell maintenance in the Ruohola-Baker laboratory, particularly focusing on metabolism. Stem cells play a critical role in development and disease; by better understanding how these cells function in both normal and pathological conditions, scientists can learn how to control, treat, and cure disorders that arise. His undergraduate research experience and his majors in biochemistry and chemistry with a minor in mathematics have convinced him to pursue a career in science. In the future, he is interested in attending graduate school and plans to further investigate the biology of disease and research cures from a biochemical, chemical, and mathematical perspective.
Mentor: Hannele Ruohola-Baker, Biochemistry
Project Title: Characterizing the Metabolic State of Cancer and Embryonic Stem Cells
Abstract: Cancer cells grow rapidly and uncontrollably, invading normal tissue and metastasizing throughout the entire body. The proliferative ability of cancer cells is reminiscent of the properties of earlier stages of development, such as embryonic stem cells. Some of the most aggressive tumors have a similar gene expression signature to embryonic stem cells. Furthermore, low oxygen concentration and hypoxic environments are common among aggressive tumors. I have shown that a link between hypoxia and the activation of stem cell markers such as miR-302 exist. Hypoxia inducible factor, HIF, a transcription factor that is stabilized in hypoxia, can change a cell’s metabolic state and induce the expression of key stem cell markers. I am now testing whether human embryonic stem cells and cancer stem cells share a characteristic metabolic signature and whether this signature is acquired by HIF activation. For this analysis, I established a quantitative real time polymerase chain reaction based assay to determine the number of mitochondria in a cell. Furthermore, I show, in both human and mouse cells, that cells earliest in development have fewest mitochondria and as development progresses, mitochondria increase. However, these mitochondria do not seem to be active. We will proceed in testing the specific stage mitochondria are activated, and the specific role of HIF in creating this unique stem-cell-like metabolic state in pathological and normal conditions.
Elliot Collins – Psychology and Romance Linguistics
In his first year as an undergraduate, Elliot developed a strong interest in language learning as he took Psychology and Linguistics classes while studying Italian. His experience in research prior to these classes eventually led him to the Cognitive Neuroscience of Language laboratory at the University of Washington. Since joining the lab 2 years ago, Elliot has worked alongside Professor Lee Osterhout and his graduate students to explore how the brain’s electrophysiological response changes as adults increased exposure to a second language. In his senior year, he will continue to explore some of the questions on language learning through the study of English native speakers learning Italian. Although he is still exploring the options, Elliot plans to enter a graduate or professional program where he can continue research in neuroscience beyond the undergraduate level. He will graduate this spring with a B.A. in Romance Linguistics and a B.S. in Psychology through the departmental honors program.
Mentor: Lee Osterhout, Psychology
Project Title: Neurobiology of Language Learning
Abstract: Event-related potentials (ERPs) are variations in brain activity measured by changes in voltage over time on the scalp. ERPs reflect the summed activity of cortical pyramidal neurons in response to a given stimulus. Although localizing the sources of an ERP signal is problematic, we propose a method for using a measure of ERP additivity to determine whether individual stimulus parameters are processed by overlapping or independent neural sources. Applying this method to language will allow us to describe the functional segregation of linguistic processing in the brain, and compare hypothetical rules of grammatical structure to those which are neurally instantiated. Additive methodologies suggest that the degree to which the mathematical sum of the waveforms resulting from a single violation approximates the waveform from the double violation indicates the independence of neurocognitive resources engaged in the processing of the respective feature. In native speakers, grammatical anomalies elicit positive deflections of the ERP waveform, peaking approximately 600ms after the onset of the stimulus. In order to further examine whether the processing of multiple types of syntactic anomalies is the result of independent or overlapping neural generators, ERPs will be recorded from native Italian speakers and native English speakers learning Italian as they read sentences, a subset of which contained article-noun pairs which were ill-formed with respect to syntactic agreement. This paradigm allows for the direct comparison of neural responses to number and gender features within a single stimulus. We propose to expand this research by exploring the neural dynamics that occur when a second language is acquired. Our additivity paradigm will make it possible to evaluate not only when rules become syntactically realized, but also whether different syntactic features are encoded individually or as a whole.
Rebecca Emery – Psychology and Philosophy
Rebecca Emery moved to Seattle from her home state of Minnesota to attend the University of Washington. After declaring a psychology major, she became a member of the departmental honors program and began working under Dr. Kevin King, a child clinical psychologist. Through working with Dr. King, Rebecca became interested in the relationship between trait impulsivity and the binge eating behavior common to bulimia nervosa. Specifically, Rebecca is interested in better understanding the role of this distinct personality construct in the etiology of bulimia nervosa in addition to how it functions to support binge eating behavior. Currently, Rebecca is a senior working towards a double major in psychology and philosophy. After graduation, she intends to pursue a doctoral degree in clinical psychology and continue conducting research in attempts to better understand abnormal behavior.
Mentor: Kevin M. King, Psychology
Project Title: Binge Eating Behavior: An Inestigation on the Moderating Role of Negative Urgency in Relation to the Dual Pathway Model
Abstract: Studies have shown that impulsivity is related to bulimic symptoms such as binge eating. However, the definition of impulsivity has been widely mixed and inconsistent throughout the literature. Recent research has shown impulsivity to consist of five distinct facets. Of these facets, negative urgency, defined as the tendency to act rashly when emotionally distressed, has been found to be related to bulimic symptoms. The proposed investigation will explore these findings in greater depth by examining the relationship between negative urgency and binge eating behavior in two different but related studies. The first study will collect data from a large sample of college female students through a web-based survey and will assess the moderating role of negative urgency on the two regulatory pathways of the dual pathway model of bulimia nervosa (i.e. dieting and negative affect). Findings from the first study will help to clarify the role of negative urgency in relation to binge eating behavior. The second study will also use a sample of female college students and will investigate the effects of negative urgency on food consumption after an experimentally induced negative mood to demonstrate a natural reaction to such a situation. Findings from the second study will attempt to provide a laboratory demonstration supporting the findings from the first study by showing that negative urgency increases binge eating within individuals. Overall, the combined results of these studies will help to inform the scientific community as to the effects of negative urgency on binge eating behavior in relation to bulimia nervosa, which may lead to clinical and therapeutic implications.
Adrian Laurenzi – Biology and Computer Science
Adrian Laurenzi first became interested in the intersection of computation and biology when he was a senior in high school. He worked on a project in at a lab at the University of Arizona to understand a plant pathway used synthesized secondary metabolites. While working at the U of A he devised a computational method that helped to identify and isolate one of the enzymes in the pathway. Almost immediately after entering UW as a freshman Adrian joined Ram Samudrala’s computational biology group to pursue his interest in computational biology. As a member of Ram’s group Adrian has worked on a number of independent projects concerned primarily with drug discovery. By integrating software developed in Ram’s group Adrian developed a computational method to identify protein targets in the malaria parasite for which an inhibitory compound would produce minimal side effects in humans. More recently Adrian has been working to apply and adapt protein structure prediction software to expressed sequence tag (EST) databases in order to improve our ability to predict the functionality of novel genes within the databases. This could accelerate the discovery of novel genes and gene networks and has important implications in medicine and drug development. In the future Adrian plans to continue his work in biomedical computation by developing open source software as an independent consultant or academic scientist. Adrian feels that creating open source software is the most effective way to make an impact as a scientist because his software will help enable the discoveries of a potentially large number of other scientists. He strongly believes in creating software that is free and open so that it is available for other scientists to use and build upon.
Mentor: Ram Samudrala, Microbiology
Project Title: Optimization of protein structure prediction software for EST data
Abstract: Large databases of expressed sequence tags (ESTs) are available containing the expressed genes from a tremendous variety of organisms. Many projects such as the Gene Index Project at Harvard University are underway, databasing the expressed genes from a tremendous variety of organisms. There are over 60 million ESTs in GenBank representing well over half of all GenBank entries. To make efficient use of EST data computational techniques have been developed to analyze and organize EST databases. ESTs have been useful in discovering new genes, understanding gene expression and regulation, and constructing genome maps, all of which have important implications in medicine. However, the utility of EST data relies upon our ability to make accurate annotations that describe the functionality of the ESTs in the source organism. Presently most approaches used to annotate ESTs rely on sequence-based comparison methods such as BLAST. This is limiting because the function of a protein is dependent upon its tertiary (3-D) structure. Therefore, the ability to reliably predict the functionality of an EST could be improved if we were able to accurately predict the structure of the proteins that ESTs encode. We have demonstrated that ProtinfoAB and Rosetta3.1 can reliably predict the structures of parts of proteins encoded by sequences that contain approximately 75% or more of the full-length protein sequence suggesting these methods would be useful in annotating at least a subset of sequences from an EST database. We propose to optimize prediction of partial structures of proteins encoded by ESTs by combining ab initio and template-based protein structure prediction methods: ProtinfoAB and ProtinfoCM. Optimization of structure prediction methods for EST data will enhance our ability to predict the functionality of ESTs enabling more informed bench experiments and expediting the discovery of new genes with potential utility in medicine.
Christopher Mount – Bioengineering
Currently a student in the Department of Bioengineering, Chris Mount’s research interests involve developing drug delivery systems to achieve targeted delivery of chemotherapeutics and contrast agents for treatment and imaging of cancer. He has pursued this research under the mentorship of Dr. Suzie Pun, also in the Department of Bioengineering. Collaborating with other researchers in the lab, Chris has recently been working to develop nanoparticles composed of a synthetic polymer for drug delivery applications. With the support of the Levinson scholarship, he hopes to elucidate the morphologies of these particles and evaluate their potential for enhancing the efficacy of anticancer agents. Following graduation, Chris plans to enter a combined M.D./Ph.D. program to train for a career in biomedical research.
Mentor: Suzie Pun, Bioengineering
Project Title: Design of polymeric filomicelles for enhances efficacy of chemotherapeutic delivary
Abstract: Despite decades of research in cancer biology, current therapeutic options for cancer patients remain limited. The administration of chemotherapeutic compounds remains one of the preeminent tools used by oncologists, but these treatments are nonspecific and tend to result in widespread systemic toxicity, limiting the maximum dose that can safely be administered. Moreover, the efficacy of these agents is limited by poor tissue penetration, multidrug resistant cancers, and solubility. Encapsulating chemotherapeutics within polymeric micelles provide one route to overcoming these challenges. Encapsulation enhances solubility, can inhibit P-glycoprotein membrane transporters responsible for multidrug resistance, and achieve specific delivery to tumor sites by exploiting the Enhanced Permeability and Retention (EPR) effect. Recent literature has highlighted the importance of micelle architecture in the effectiveness of polymeric micelle drug carriers, with notable attention to filament-type micelles, or filomicelles. We propose the use of polymeric filomicelles consisting of a poly(ethylene oxide) -poly(hydroxybutyrate) diblock copolymer for encapsulation of the chemotherapeutic doxorubicin to enhance its efficacy as an anti-cancer agent. Diblock composition will be designed to achieve optimal doxorubicin content, release kinetics, and cytotoxic efficiency in vitro. Doxorubicin-loaded filomicelles are anticipated to display enhanced chemotherapeutic efficacy against multidrug-resistant cancerous cell lines and exhibit enhanced tissue penetration ability in three-dimensional multicellular spheroid tumor models. This research is therefore expected to contribute a valuable, novel delivery vehicle for enhancing the effectiveness of chemotherapeutic agents.
Daniel Kashima – Neurobiology and Music
Daniel Kashima entered the University of Washington as a music major and one who enjoyed learning about Biology. Over his first two years as an undergraduate, he developed a heightened passion for learning more about the brain and thus applied and also was accepted into the Neurobiology program. The idea of conducting research in this area intrigued him and he feels fortunate to be accepted as an undergraduate researcher in the laboratory of Dr. Ed Rubel in his third year.
Dr. Rubel’s lab attracted Daniel as the research there focuses on auditory neuroscience. This effectively allows Daniel to bridge his two passions. His research uses techniques in molecular biology and physiology to uncover more information on the chicken sound localization circuit. Currently, he is using immunohistochemistry to look for an expression gradient of Eph receptors/ephrins along the midline of the chicken auditory system through development.
In his fifth year, the research component of his education continues to fascinate Daniel. He is currently trying to decide on what post-undergraduate path to pursue. Whether as an M.D., PhD, or both, research will undoubtedly be a major part of his future.
Daniel will graduate from the College Honors Program this Spring with degrees in Neurobiology and Music (classical guitar).
Mentor: Edwin Rubel, Otolaryngology-HNS
Project Title: The Role of Eph/ephrins in Axon Sorting in the Avian Sound Localization Circuit
Abstract: Auditory brain nuclei are organized in a tonotopic manner: the sound frequency to which neurons respond best, progressively and predictably shifts with its anatomical position, preserving the neighbor relationships of the auditory sensory epithelium, the cochlea. In birds, the bilateral nuclei n. magnocellularis (NM) and n. laminaris (NL). both part of a circuit responsible for sound localization, are arranged tonotopically. In each nucleus. neurons in the caudolateral region respond best to low frequencies (LF) and those in the rostromedial region respond best to high frequencies (HF). Our results show that axons projecting from NM to NL, thereby crossing the midline and forming the crossed dorsal cochlear tract (XDCT), are also arranged tonotopically. The mechanism governing this arrangement during development, however, is unknown. Studies done on the visual and olfactory systems implicate an expression gradient of Eph receptors and ephrins to form topographic axonal pathways. Although these molecules have been shown to be expressed in the chick auditory brainstem, no effort has been made to look for a gradient in expression in the XDCT. In order to address this, we will build on our results and look for a molecular gradient in XDCT. We will prepare parasagittal slices of chicken brainstem containing XDCT of 4 different developmental stages and use immunohistochemical methods to look for gradients in EphB2, EphB5, and ephrin-Bl expression. The slices will be imaged using widefield and confocal microscopy. Parasagittal sectioning incorporates the entire tonotopic extent of the XDCT into single slices such that protein expression levels will be compared within single slices. The presence of a gradient in Eph/ephrin expression will provide further insight into a possible mechanism underlying the tonotopic arrangement of the XDCT during development and can serve as a model to study the influence of molecular markers on axon sorting.
Sherry Lee – Molecular, Cellular, and Developmental Biology
Encouraged by her lab’s strong support, Sherry Lee wants to learn more about cancer etiology in order to better understand how it ravages the human body. Thanks to her mentor, Dr. Paul Nghiem, Sherry has realized that a career in medicine is truly gratifying not when a physician simply prescribes readily available drugs, but when a physician can propose and test a more effective therapeutic treatment. Currently, Sherry is investigating the functional relevance and role of microRNA gene regulation in a deadly form of skin cancer called Merkel cell carcinoma. As a Mary Gates Research Scholar and a Levinson Scholar, Sherry hopes to rely on her family’s, her lab’s, and the foundations’ support to achieve beyond their expectations. Overall, her undergraduate research experience has led her on a promising path to pursue a career in translational medicine. She plans to attend a Medical Scientist Training Program after graduation to continue biomedical research.
Mentor: Paul Nghiem, Medicine-Dermatology and Pathology
Project Title: A Merkel cell polyomavirus-encoded microRNA expressed in human Merkel cell carcinomar
Abstract: Merkel cell carcinoma (MCC) is a rare but lethal skin cancer that is associated with immune suppression. People immunosuppressed with AIDS are twenty times more likely to get MCC. Merkel cell polyomavirus (MCPyV), an immunogenic virus, causes more than 70% of MCC. However, 90% of MCC patients have no identifiable immune suppression. In this population, MCC tumors proliferate by escaping the immune system, perhaps with the help of MCPyV. One potential mechanism the virus employs to escape the immune system is through microRNAs (miRNAs), small noncoding RNAs that downregulate the expression of genes that might be recognized by host immune system. During the early stage of my research project, I helped to discover a Merkel polyomavirus-encoded miRNA and to quantify expression of the Merkel-miRNA in MCC tumors. The Merkel-miRNA was expressed in strongly virus positive tumors (n= 11) and not expressed in virus negative tumors (n=4). Also, I detected MCPyV DNA in MCC patients’ blood samples. Because the Merkel-miRNA was predicted to downregulate lymphocyte genes, I hypothesize that it will be present in the blood. For aim 1, I will test blood samples for Merkel miRNA expression. Furthermore, I used a validated in silico algorithm called TargclScan to predict the Merkel-miRNA’s human target genes, which are mostly important for immune functions. For example, the gene PSME3 activates the immunoproteasome, which triggers immune responses. I hypothesize that these target genes will be downregulated in virus positive cells. I will quantify expression of Merkel-miRNA target genes in miRNA-positive cells in aim 2. These two aims are essential components to understanding viral genetic control in MCC pathogenesis.
- Detect Merkel-miRNA in blood samples from MCC patients
- Quantify gene and protein expressions of Merkel-miRNA target genes in cell line after transfection with Merkel-miRNA
Catherine Louw – Biology and Biochemisty
Catherine Louw’s interest in performing scientific research was inspired by a summer session at the Seattle Biomedical Research Institute. This experience soon led her to embark on her laboratory experience in the Baker lab, after being intrigued by the idea of computational protein design. Catherine began working with graduate student Justin Siegel on a novel project, aiming to enhance the efficiency of a computationally designed enzyme that could one day be used in a pathway for carbon dioxide fixation. She has developed a high-throughput screening protocol to grow and assay potential hits in a fraction of the time that it would normally take. Catherine is currently a senior at UW, pursuing a dual degree in Biology and Biochemistry. After graduating she hopes to attend medical school to become a doctor in family medicine were she plans to utilize her experiences with research methodologies in order to better understand and incorporate new medical discoveries into her practice.
Mentor: David Baker, Biochemistry
Project Title: Enhancement of a Computationally Designed Enzyme: A Contribution to the End of Global Warming
Abstract: Global warming is a pressing issue worldwide and finding new ways to control excess carbon dioxide is becoming increasingly important. This study aims to develop a novel biological system which converts carbon dioxide into small sugars. To create this system, a new metabolic pathway is being constructed which employs six naturally-occurring enzymes and one computationally-designed enzyme called Formolase. Formolase is derived from a naturally-occurring enzyme, Benzaldehyde Lyase, which ligates two benzaldehyde molecules together, while the desired reaction of Formolase is to ligate three formaldehyde molecules together to create dihydroxyacetone. A computer program called Rosetta was used to create Formolase, identifying four mutations to make within the active site in order to drastically alter substrate specificity. The enzyme would now catalyze the polymerization of formaldehyde over that of benzaldehyde, and when tested, these mutations altered specificity as predicted. In order to further understand this change in specificity, I determined the contribution of each mutated residue to the activity on formaldehyde. This study illuminated the key mutations necessary to maintain desired activity, as well as mutations which could be changed in the future to improve the activity of the enzyme. Although Formolase demonstrates enhanced activity on formaldehyde, the activity must be increased further before it can be used in the metabolic pathway. Therefore, I am now working on mutating additional residues in order to enhance activity. We also plan to alter the structure of the protein by adding new loops and tails to form more contacts with the formaldehyde ligand, which we hypothesize, will further improve our enzyme. Once sufficiently active, Formolase will complete the novel metabolic pathway and provide an alternative method for converting carbon dioxide into a more useful material. In this way, global warming can be controlled and the amount of carbon dioxide in the atmosphere decreased.
Alyssa Sheih – Bioengineering
As a student in the Bioengineering department, Alyssa Sheih’s research interests involve addressing current medical problems through new diagnostic methods and therapeutics. Her passion for this area led her to Professor Hong Shen’s lab in the Chemical Engineering department, as a 2008 UW Amgen Scholar. Since then, Alyssa has been studying the design of drug delivery systems and their interactions with the immune system. Currently, she is excited for the opportunity to study cell-based therapy for neurodegenerative disease, with the funding of the Levinson scholarship. After graduation, Alyssa plans on pursuing a Ph.D. degree in Bioengineering with a research focus on immunology.
Mentor: Hong Shen, Chemical Engineering
Project Title: Engineering T Cells for Brain Imaging and Therapeutics
Abstract: According to the Alzheimer’s Association, every 70 seconds, someone in America develops Alzheimer’s disease. Beta-amyloid peptides are believed to be the main cause of this disease, forming plaques between nerve cells and triggering inflammation. By destroying brain cells, Alzheimer’s causes severe problems with memory, thinking, and behavior. Currently, diagnostic capabilities for this disease are limited with physicians utilizing neurological exams and brain imaging. Because early diagnosis of Alzheimer’s disease and clinical evaluation of therapeutics is important, there is a need for an accurate diagnostic tool for Alzheimer’s disease. Here we propose using a contrast agent for brain imaging that can bind to beta-amyloid peptides, allowing for the detection of Alzheimer’s disease. Previously, non-cellular vehicles such as nanoparticles have been used to deliver contrast agents to the brain, by targeting receptors on the blood brain barrier to achieve transport. However, other types of cells also express these receptors, resulting in nonspecific targeting of the brain. These particles can be immunogenic and are vulnerable to clearance by our immune system. Here we propose another solution by using T lymphocytes, which are immune cells capable of crossing the blood brain barrier and localizing near sites of inflammation in the brain. These cells will serve as vehicles modified to carry a contrast agent along with antibodies specific for beta-amyloid peptides. Initially, a proof of concept study will be completed to show that the surface of T cells can be modified to carry a fluorescent label and an antibody for ovalbumin, a more available protein that will serve as a substitute for beta-amyloid peptides in these experiments. This surface modification procedure will be optimized to maximize the binding capability of T cells without compromising its functionality. This project presents one of the first steps towards developing an accurate diagnostic tool for Alzheimer’s disease.
Mark Shi – Neurobiology and Biochemistry
When Mark Shi first came to the University of Washington, he was unsure of what he wanted to study and pursue as a career. That all changed while he was taking introductory biology, where he became fascinated with the intricate, behind-the-scene mechanisms that mediate our daily lives. Mark pursued this interest by joining the neurobiology program, where he had the opportunity to learn about one of the most complex and least understood systems of the human body. After his first year in the program, Mark began working in Dr. Bosma’s developmental neurobiology lab. This research has allowed Mark to expand on his knowledge of the nervous system by investigating new questions in the field. After graduating this year, Mark plans on continuing his research in Dr. Bosma’s lab while applying for medical school. He hopes to further develop his investigative research skills with the support of the Levinson Scholarship as he pursues a career as a physician.
Mentor: Martha Bosma, Biology
Project Title: Activity-Dependent Regulation of 5HT-Postitive Raphe Neurons in Developing Mouse Hindbrain
Abstract: In many regions of the developing nervous system, spontaneous synchronous activity (SSA) plays a role in synaptogenesis, cell positioning, ion channel development, and neuronal migration. SSA has been observed in the hindbrain, the most caudal of the three primary divisions of the developing vertebrate brain that develops into the cerebellum, pons, and medulla. These regions coordinate complex muscular movements, equilibrium, and autonomic functions. In previous studies, our lab has identified an internal pacemaker, which drives SSA during a discrete window of time during embryonic development; this pacemaker region is a cluster of serotonergic (5-HT) neurons located between rhombomeres (r) 2 and 3. We are currently examining the mechanism by which SSA develops in the hindbrain. Using intracellular calcium imaging to visualize electrical events, we have observed SSA primarily propagating rostro-caudally along the midline of hindbrains at embryonic day (E) 11.5. Culturing hindbrain tissue from E10.5 to E11.5 has allowed us to pinpoint requirements for SSA in vitro. We have shown that hindbrains cultured in the presence of ketanserin, a blocker of the 5-HT2 receptor, have SSA with reduced frequency at E11.5, and fewer 5-HT-positive neurons, as shown with immunocytochemistry. Tissues cultured in high concentrations of extracellular potassium or Valproic Acid (VPA), the latter of which is a model for autism in mice, exhibit an increased frequency in SSA. Furthermore, tissues cultured with VPA have SSA with greater amplitude that extends beyond the midline to lateral regions. We therefore postulate in this model of cultured hindbrain that activity itself is able to regulate the appearance and excitability of the cluster of 5HT-positive pacemakers that drive SSA in the hindbrain.
Kate Buckley – Bioengineering
Kate Buckley’s strong interest in cardiac repair began when she was introduced to the field by her mentor, Dr. Mike Regnier. Kate has been passionate about research since she arrived in the lab in the fall of her freshman year, and is motivated by a continuing interest in the therapies she investigates and the constant need for translational research that aims to address current health problems. Kate is particularly interested in creating genetic and cellular therapies in cardiac muscle that could be applied to different types of heart disease. The Levinson Scholarship has given her the opportunity to explore a novel research question that will allow her to delve deeper into the exciting opportunities that research offers.
In addition to research, Kate enjoys traveling and being actively involved in the Bioengineering program and the Honors Program. Kate is an avid learner and is constantly seeking new applications for her training as a bioengineer and research scientist.
After graduating, Kate plans to attend graduate school to continue her work with cardiac repair. She aims to one day perform clinically applicable research and teach students in the field of bioengineering and physiology.
Mentor: Mike Regnier, Bioengineering
Project Title: Gene therapy and the adrenergic response: L48Q cTnC virally transduced adult cardiomyocytes.
Abstract: Heart disease is the leading cause of death in the United States. After a heart attack (one of the most common results of heart disease), the heart undergoes an extensive remodeling process when normal cardiovascular function is disrupted. At the University of Washington exciting new therapeutic strategies are being developed to that improve and repair heart function. Gene based therapies that target cardiac myofilaments offer a way to halt or even reverse this process by altering contractile properties of the heart. Genetic transfer of the mutant L48Q troponin C offers potential as a therapeutic tool to improve function of surviving myocardium by enhancing Ca 2+ triggering of contraction. However, if this therapy is to be useful following an infarct, it must allow the ability for the heart to respond to adrenergic stimulation under stress. This project will investigate the adrenergic response of infarcted and non-infarcted myocardium with L48Q cTnC transfection into the myofilaments. Using cultured adult rat heart cells, the levels of adrenergic stimulation will be varied and the response characterized by measuring the changes in contraction and relaxation parameters. Contraction measurements will be made on individual cardiomyocytes using video microscopy coupled to computer software that measures cell and sarcomere length changes. After completing studies in cultured cardiomyocytes, this study will extend to an animal model of gene transfection to study the effect of L48Q cTnC and the adrenergic response at the in vivo and whole organ level. These studies are essential to determine if this gene therapy has the potential to be clinically relevant and reduce changes leading to heart failure. If so, L48Q cTnC has great potential as a therapeutic tool for several forms of cardiac disease.
Lauren Hanson – Neurobiology & Public Health
Growing up the daughter of two physical therapists instilled a passion for health and a curiosity about the human nervous system in me early on. When I began my first quarter at the University of Washington I had my sights set on pursuing a career in medicine but felt completely lost in how to successfully achieve that end. My intense desire to understand the intricacies of the correctly and incorrectly functioning human body inspired me to apply for entrance into the neurobiology program in my sophomore year. Early admittance into this program has allowed my neurobiology courses to serve as a foundation for my academic experience as an undergraduate. Through my neurobiology studies I found my true passion and have since forged what I know is the right path for me as an undergraduate. Following the first year of this program I actively sought a place in Dr. Moody’s lab knowing that his developmental neurobiology based research was something I wanted to pursue. My passion for the research I have been conducting over the past year and a half is driven both by my inquisitive nature and by the possible clinical applications my work may have for disorders in humans . An understanding of correct brain development has the potential to facilitate an understanding of later development when the mechanisms I study may contribute to pathological forms of brain activity such as seizures.
Mentor: Dr William Moody, Neurobiology
Project Title: Initiation Mechanisms of Spontaneous Synchronous Activity in Neonatal Mouse Cortex
Abstract: Spontaneous Synchronous Activity (SSA) plays a central role in mammalian nervous system development. In mouse cortex, SSA is vital for the development of neuronal characteristics necessary for normal information processing. For SSA to carry out its developmental functions and mature firing properties to emerge, it must begin and end within a critical temporal window. As such, how the timing and generation of SSA are controlled is a major question in neurobiology. The Moody lab has determined that a discrete pacemaker region in mouse cortex controls SSA. The question about pacemaker function has been approached from three different directions: multi-cell calcium imaging of neuronal activity, molecular studies of ion channel types, and direct electrophysiological recording from single neurons in living brain slices. My work thus far has used the technique of single-cell electrical recording, patch clamp, because it provides access to the most direct information about pacemaker mechanisms via single cell behaviors and responses. A likely candidate for a pacemaker current is the low-threshold inactivating (T-type) Ca2+ current so we have investigated the role this current plays in SSA using the three previously mentioned experimental approaches. Molecular studies of ion channels have shown that the T-type Ca2+ channel protein is highly concentrated in the ventro-lateral pacemaker region which matches the point of origin of SSA waves detected in our multi-cell calcium imaging experiments. Additionally, imaging experiments have shown that Mibefradil, a T-type Ca2+ blocker, blocks SSA. My previous patch clamp recording analysis comparing pacemaker and follower neurons shows significantly longer burst durations in pacemaker neurons, which is consistent with the presence of T-type Ca2+ currents. From these findings my future experiments will attempt to further elucidate the mechanisms of pacemaker initiation of SSA in mouse cortex using single-cell electrical recording to isolate the T-type Ca2+ current in voltage clamp recordings. I will also investigate the effects of Mibefradil on SSA in single cells in the pacemaker and follower regions and determine if the pacemaker quality of the initiation zone is a function of a network property or individual pacemaker qualities of the discrete component cells.
Rita Sodt – Computer Science
Rita Sodt began her research during her first year at the University of Washington. She thinks getting involved with research early on in her undergraduate studies was one of the best decisions she made because it has really enriched her undergraduate experience and helped her discover where her interests lie. Rita came to work in the Swanson lab because she was excited by its unique approach to cancer research. Using a mathematical model to simulate brain tumor growth it is possible to make predictions about how a tumor would spread; predictions that can lead to improved tumor treatments. Early on in her research, Rita gravitated towards the programming problems in the lab, including image analysis and simulations of tumor growth, and decided to major in computer science. She loves working in an interdisciplinary research setting, especially because as she is working on a computer science related project she gets to learn new things all the time about applied math and biology, and understand the big picture behind the research. She plans to pursue graduate studies in computer science and continue research related to computer science and health care.
Mentor: Dr. Kristin Swanson, Pathology
Project Title: Simulation of Anisotropic Growth of Gliomas Using Diffusion Tensor Imaging
Abstract: Gliomas are highly invasive brain tumors that account for nearly half of all primary brain tumors. Since current medical imaging techniques only detect a portion of these cancerous cells, a computational model was developed by Dr. Kristin Swanson to give more information about the extent of the tumor invasion below the threshold of imaging and to give a prediction of glioma growth that can be tailored to individual patient’s tumor. This computational model is currently based on two elements: cell proliferation and isotropic cell diffusion. Isotropic diffusion assumes that cell migration is random, however it is commonly accepted that glioma cells migrate preferentially along the direction of white matter tracts. In order to account for this observed diffusion, I will write a program that calculates the growth of gliomas that includes anisotropic diffusion. To do this I will use a published technique utilizing diffusion tensor imaging (DTI) to show the directional orientation of brain matter throughout the brain, which indicates the direction that glioma cells tend to migrate. My project will result in an improved mathematical model that can be used to simulate 3D virtual tumors. Hopefully after modifying the model to include anisotropic cell diffusion, the simulated tumors will more closely predict the growth of tumors that we observe in vivo. I will compare the results of our simulations to observed tumor growth to determine how well the model predicts the growth of gliomas.
Kathryn Winglee – Computer Science, Microbiology
Kathryn Winglee is interested in infectious diseases, but she is also intrigued by technology and its applications to biological research. As a double major in computer science and microbiology, she hopes to use her skills in both fields to study pathogens and how they cause disease. She began doing research the summer after her high school graduation, building a microfluidic device to perform PCR then studying hepatitis C before joining the Ramakrishnan lab. Her research on tuberculosis in the Ramakrishnan lab, where she has written a program capable of tracking fluorescent objects in 3D, has allowed her to both create and apply new technology to the study of a major global disease. She also has experience as a TA for the general microbiology lab. Her plan is to continue with similar research in graduate school.
Mentor: Lalita Ramakrishnan, Microbiology
Project Title: Changes in Infected Macrophages During Tuberculosis Pathogenesis and Granuloma Formation
Abstract: Tuberculosis (TB) is a bacterial disease that causes nearly two million worldwide deaths every year. One important characteristic of this disease is the formation of granulomas, aggregations of infected macrophages and other immune system cells, in the infected host. Understanding how granuloma formation in TB infections occurs is vital to understanding this disease. One animal model of TB makes use of zebrafish embryos infected by Mycobacterium marinum, a close relative of Mycobacterium tuberculosis, the causative agent of human TB. Zebrafish embryos are transparent, allowing real-time observation of the course of infection. In previous quarters, software has been created to track fluorescent M. marinum as it is carried inside macrophages during infection. This program will be used to study the movements and characteristics of macrophages during infection. By combining the use of fluorescent M. marinum and host immune cells with this program, the effects of carrying intracellular bacteria on macrophage motility, as well as the characteristics of macrophages that form and maintain granulomas, will be investigated. Finally, these studies will be extended to the effects of different bacterial mutations on macrophages during pathogenesis. The results will provide a better understanding of how pathogenic mycobacteria interact with their host to cause one of the world’s major diseases.
Joan Bleecker – Chemistry
Joan now hails from Gig Harbor, WA, but has lived all over the United States. She has wanted to attend the University of Washington since she was 10 years old.
The summer of her freshman year, Joan was given an opportunity to perform research in the Dovichi Lab working with breast cancer cells, and has been researching ever since. She cannot say enough for the importance of research for any would-be-chemist. After all, knowledge is nothing without practical application.
Research has also given Joan the chance to present her work all over the country. She enjoys these trips immensely, even though she has a tendency to get incredibly nervous before speaking in front of others.
Joan’s chemistry career began with an amazing high school chemistry teacher. She believes it is important that young students get a good introduction to chemistry. Joan tutors at the University of Washington’s CLUE center and for the Youth Tutoring Program (YTP) in Jackson Park. After getting her degree in chemistry, she hopes to teach chemistry for a few years before attending graduate school to pursue her Ph.D.
Mentor: Norman Dovichi, Chemistry
Project Title: Protein fingerprinting of MCF-7 breast cancer cells
Abstract: Breast cancer is leading cause of cancer mortality for women in the United States. Prognostic indicators like progesterone receptor and Her2/neu proteins guide treatment and predict outcomes. Their expression levels directly affect patient survivability. Even with these indicators, there is a need for more detailed information to guide therapy. By generating protein fingerprints, which show the expression levels of multiple proteins at one time, our lab hopes to provide a valuable prognostic tool for cancer patients. MCF-7 is an established breast cancer cell line. By dosing MCF-7 with the chemotherapeutic agent mitomycin C (MMC), we hope to isolate survivor populations for protein studies. Cell viability will be determined by hemocytometry with Trypan blue staining and flow cytometry. Proteins in the survivor cell lines will be analyzed using 2D SDS PAGE/LC-MS and capillary electrophoresis with laser-induced fluorescence detection.
Jeff Bowman – Oceanography & Biology
Following an army enlistment and two years at Bellevue Community College I transferred to the School of Oceanography at the University of Washington. The School of Oceanography has a very strong tradition of involving undergraduates in research, and I soon found a position in the lab of Prof. Julian Sachs. In spring 2007 I had the opportunity to help plan and conduct an expedition to a region of Canada known to contain many hypersaline lakes and to the Great Salt Lake of Utah. During this expedition I became very interested in the density and diversity of microbial life present within these harsh environments. After our return I began planning a project to enumerate and isolate extreme halophiles from some of our samples in order to identify a potential salinity indicator in the form of a lipid biomarker.
Mentor: Julian P. Sachs, Oceanography
Project Title: Enumeration and isolation of culturable halophiles from several hypersaline lakes and the development of a potential salinity indicator
Abstract: Halophiles recovered from hypersaline environments in western Canada and Utah’s Great Salt Lake provide an opportunity to advance our knowledge of how these organisms interact with their harsh environment. By treating these organisms to both aerobic and anaerobic, and light and dark conditions we can reduce competitive inhibition among culturable halophiles and enumerate the widest variety possible. Isolation of morphospecies cultured in this manner will enable us to determine the salt tolerances for individual species by inoculating pure colonies onto media of varying salinities. Analysis of lipid biomarkers produced by halophiles cultured at these varying salinities using gas chromatography mass spectrometry may reveal salinity indicators that can be applied to paleoclimate questions.
Lauren Hanson – Neurobiology & Public Health
Lauren Hanson is interested in the development of the human brain and the causes and treatment of neurological disorders. Having entered the neurobiology program a year early, Lauren gained the background and skills to immerse herself in the research that she is most passionate about for the remaining three years of her program. Lauren’s mentor describes her as the top student in her cohort in the neurobiology program; she is someone who produces the highest quality work in every aspect of her education. In terms of the goals of the Levinson scholarship, he says: “I cannot imagine a better candidate than Lauren. She really is an ‘emerging scholar’ in the best sense of the award. Granting her this award will enable an unusually talented student to experience a real long-term research project in a way that few students have the opportunity to do.” Lauren’s award will provide her with scholarship support, research books and supplies and conference travel.
Mentor: Professor William Moody, Department of Biology, Chair of Neurobiology
Project Title: Physiological properties of pacemaker neurons driving spontaneous activity in the neonatal mouse brain
Abstract: Spontaneous electrical activity plays a central role in nervous system development. In mouse cortex, spontaneous synchronous activity (SSA) is vital for processes such as the formation of appropriate synaptic connections and development of normal neuronal properties. For SSA to carry out its developmental functions, it must occur during the appropriate critical stages of development. SSA must also cease to provide for the correctly timed emergence of the mature information-processing functions of neurons. Therefore, how the developmental timing and generation of SSA are controlled is a major question in neurobiology. It has been determined that SSA is run by a pacemaker region in mouse cortex. By utilizing calcium imaging, extracellular recording, and whole cell recording techniques on mouse brain slices, I plan to learn a great deal about the specific location, characteristics, development and control of the pacemaker region responsible for SSA. I will identify the population of neurons that compose the pacemaker region and begin by investigating its developmental emergence. From this stems my investigation of the unique properties of the pacemaker cells. Understanding the emergence of the pacemaker function and the ways in which it controls the onset, activity, and cessation of SSA is vital in understanding the mechanisms of brain development. Continued exploration of the pacemaker region also has potential to improve understanding of later development when it may contribute to the mechanisms of pathological forms of synchronous activity, such as seizures.
Jonathan Keller – Biochemistry
I first became interested in protein research during an honors biology seminar, studying the Ice Worm and the various adaptations that allow it to thrive in frozen environments. I was particularly intrigued by the protein modifications suited to low temperatures, structural variations that enhanced functionality in sub-zero climates. I was interested in further pursuing protein research, especially as it related to the medical field, and began working in the lab of Dr. Rachel Klevit. The Klevit Lab studies the breast cancer susceptibility protein BRCA1 using high resolution structural biology techniques such as Nuclear Magnetic Resonance (NMR). The research offers powerful insight into the structural and functional properties of BRCA1 and has profound implications in developing far more precise and effective cancer therapy.
My hope is to attend medical school and eventually pursue a career that incorporates both patient care and biomedical research. I am especially interested in pursuing cancer research, as the field is still just beginning to understand the complex biochemical interactions involved in such a wide array of pathologies. My current experiences in the Klevit lab studying BRCA1 are invaluable to that development. The knowledge and skills I have gained since beginning research are fascinating and have enhanced my understanding of biochemistry through intensified, hands-on application.
Mentor: Rachel E. Klevit, Biochemistry
Project Title: BRCA1-mediated ubiquitination
Abstract: The breast cancer susceptibility gene, BRCA1, encodes a crucial tumor suppressor protein involved in multiple DNA damage repair pathways. One of its most important functions is ubiquitin ligase activity, in which BRCA1 facilitates the transfer of the small protein ubiquitin to other protein substrates. The ubiquitin acts as a molecular tag, important for marking substrates in many cellular processes such as proteolysis, cell signaling, and DNA repair. The loss of ubiquitin ligase activity when BRCA1 contains cancer-associated mutations suggests an important role for this function in tumor suppression capacity. The various steps of ubiquitination also require adaptor proteins in addition to BRCA1 to successfully mediate ubiquitin transfer. The process by which the proteins interact, and why mechanistically the adaptors are necessary for transfer, is still unknown. The use of high resolution structural biology techniques, such as Nuclear Magnetic Resonance (NMR), offers powerful insight into the three dimensional characteristics of BRCA1-protein complexes. Structural elucidation will furthermore provide insight into the physical relationship and function of each interacting component, and expectantly lead to more precise treatment possibilities for breast cancer, the second most common cause of cancer related death in women.
David Linders – Bioengineering
My research experience started my freshmen year as I began working in the Applied Biomechanics Laboratory. We performed biomechanics testing on macaque monkey specimens in an attempt to understand the developmental changes in the cervical spine as a function of age. From there, I was invited to help engineer the force sensing glove I am currently involved with. It is an exciting opportunity to be creative and analytical while developing a device that will be practical and effective in physical medicine. The potential for this device to change the way clinicians obtain and share their results is exciting and motivating.
Mentor: David J. Nuckley, Mechanical Engineering
Project Title: Clinical Force-Sensing Glove
Abstract: For many clinicians, their effectiveness is dependent on the forces they apply to their patients. However, current care strategies lack quantitative feedback. My objective is to develop a force-sensing glove to provide real-time quantitative feedback to assist in clinical diagnosis and treatment. To minimally affect a clinician’s function, obtain maximal signal to noise in a medical environment, and maintain patient safety, I am currently developing a fiber optic sensor and methods for implementing it in a latex glove. When a fully functional instrumented glove is fabricated and calibration tests are performed, I plan on presenting the glove to various clinicians for a field test this spring.
Christine Masuda – Neurobiology
Christine’s interest in medical research began with a histology project in high school and has deepened throughout her undergraduate years. She was her high school valedictorian, and won a prestigious Washington Scholars award for tuition at any college or university in the state as a high school senior. Her ultimate goal is to become a physician-scientist, linking clinical medicine and basic biology. She states: “I want to practice medicine with the analytical skills learned from research and to conduct research with human faces behind my motivation.” Her mentor ranks her among the very best students he has taught, speaks highly of Christine’s talent for research, and the critical timing of this award: “I believe that Christine has reached a defining moment in her undergraduate training as she embarks on an increasingly independent trajectory.” Christine’s award will provide support for research supplies and conference travel.
Mentor: Prof. Peter Rabinovitch, Department of Pathology
Project Title: Possible neuroprotective effects of mitochondrially-targeted catalase in the 3-NP model of acute oxidative stress
Abstract: There is considerable evidence that oxidative stress, resulting from exogenous and endogenous free radicals, has a causal role in aging and age-related disease, in particular, neurodegenerative diseases. The mitochondria have been shown to be the foremost site of endogenous free radical production. To further investigate this, we will study a transgenic mouse that expresses human catalase (an antioxidant enzyme) that is targeted to the mitochondria. This transgenic mouse demonstrates a 20% increase in life span and decreases in age-related pathology in the heart and possibly skeletal muscle. While there is research underway focusing on heart and skeletal muscle, this project will specifically relate to the brain, which has not yet been examined. One model that can test the importance of mCAT expression in the brain is the 3-nitropropionic (3-NP) model of acute oxidative stress. 3-NP is an irreversible inhibitor of succinate dehydrogenase, complex II in the electron transport chain of the mitochondria. 3-NP has been used by other investigators to recapitulate the clinical features of Huntington’s Disease, another age-related neurodegenerative disorder. These investigators have demonstrated that 3-NP produces selective striatal lesions that are attributed to neurotoxic effects of oxidative damage. In this study, we will investigate the possible neuroprotective effects of the mCAT compared to WT in the 3-NP model.
Lauren Palmer – Biology & Microbiology
Lauren came to the UW for her undergraduate degree specifically because of the research opportunities offered for undergraduates. She has the unique experience of having been involved in research since the summer before her freshman year, working on two projects that explore cellular metabolism. She is very interested in a future that combines academic and biotechnology research and hopes to participate in academic-industry collaborations. Her mentor describes how Lauren has become an important member of her research group: “Not only has she significantly advanced her project, but she has also been instrumental in setting up and trouble shooting protocols for the lab…Her future work in uncovering the link between methanol metabolism and glutathione homeostasis is very important for our understanding of methylotrophy and the engineering of this organism for biotechnological and industrial use.” She adds: “She is one of the top students I have mentored and I have no doubt that she will have an outstanding scientific career and make a lasting contribution to science.” Lauren’s award will provide scholarship support, books, and conference travel.
Mentor: Professor Mary Lidstrom, Department of Chemical Engineering & Microbiology and Vice Provost for Research
Project Title: Metabolic Studies in Methylobacterium extorquens AM1
Abstract: Methylotrophs, or organisms that can grow on single-carbon compounds, have great potential for bio-industrial applications. Methylotrophs can be bioengineered to produce value-added products from methanol, a cheap and environmentally benign carbon source. Due to the interrelated nature of metabolism, successful engineering requires deep understanding of the organisms’ metabolism. We seek to further understanding of methylotrophy through study of the model methylotroph, Methylobacterium extorquens AM1. Building on the body of knowledge of methylotrophic pathways, my work seeks to elucidate links between methylotrophy and other metabolic networks. Previous results suggest strong links between methylotrophy and iron metabolism. My work will explore the differences in iron metabolism during methylotrophic and non-methylotrophic growth in AM1, including assaying iron requirements and characterizing iron-related proteins and mutants. This work will aid in the understanding of methylotrophic growth and general iron metabolism.
Teresa Peterson – Bioengineering
Teresa began her research experience she will was just a junior in high school. She was one of 14 students involved in a summer program called Lab Experience for the High School Student, which was created specifically to introduce high school students to the new and blossoming field of bioengineering. Since then, Teresa has been an active student researcher here at the University of Washington.
Her other activities include being a committee member for Relay for Life, and other cancer related organizations. She writes, “I regularly speak with the community about the importance of the work done by the American Cancer Society and how contributing to Relay for Life will affect the lives of millions of current and future cancer survivors. Before working with the American Cancer Society and Relay for Life, I had never understood just how devastating a disease cancer is.”
In the upcoming future, Teresa hopes to attend a graduate program where she can continue her research. She would like to seek a career in research where I can work towards making cellular and molecular treatments for cancer a clinical reality.
Mentor: Suzie Pun, Bioengineering
Project Title: Surface-modified Listeria-monocytogenes as a carrier for the intracytosolic delivery of therapeutics
Abstract: Macromolecule therapy, the introduction of therapeutic agents into diseased cells in the body, has the potential to revolutionize the treatment of life-altering diseases like cancer. One of the major needs in delivery to tumors is the development of carriers that can efficiently transport therapeutic agents into tumor cells. Listeria monocytogenes, a facultative intracellular pathogen, is a promising potential carrier because it is highly efficient at entering the cytosol after invading host cells. It is also capable of moving through and between cells, giving it the potential to make its way past the most accessible layer of the tumor, reaching deeper, central cancer cells for delivery. Attenuated strains of Listeria are of interest for intracellular therapeutics delivery. To deliver therapeutic genes to tumor cells, I propose to attach them to the surface of Listeria via a streptavidin-biotin linkage. I have developed a surface conjugation strategy that allows modular attachment of therapeutic cargo to Listeria. Listeria were surface-modified by reaction with NHS-biotin, enabling the attachment of biotinylated cargo through a streptavidin linker. Surface biotinylation of Listeria was confirmed through a plate-binding assay. Biotinylated Listeria bound to a plate displaying surface-adsorbed streptavidin, while unmodified Listeria failed to bind. The attachment of a biotinylated, fluorescently-labeled model protein cargo to the surface of biotinylated Listeria was examined, and the invasion of host cells by this Listeria-protein conjugate was investigated using fluorescence microscopy. I will further demonstrate delivery to the cell cytosol and begin investigation of cargo loading characteristics and cell cytotoxicity. This method will then be translated to a less pathogenic strain of Listeria and I will demostrate its ability to deliver antigenic peptides and stimulate T-cell activity. Listeria-drug conjugates in the future could be applied toward nucleic acid and protein delivery.