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The Washington Research Foundation Fellowship

Dan Minter, Neurobiology, 2011-12 WRFF

Dan Minter photoWithout doubt, the greatest decision that I made during my education was to study neurobiology. Ever since beginning this major, I have found myself absolutely gripped by fascination and interest in the complex neural structures that underlie our behavior, thoughts, and actions. Yet more that, I am extremely appreciative of the many amazing opportunities that the NBIO program has afforded to me and my classmates.

Starting in June 2010, I began to work in the laboratory of Dr. William Moody, the director and founder of the undergraduate NBIO program. As part of this experience, the other undergraduates and I were able to learn a variety of new techniques as we studied the role and nature of spontaneous waves of electrical activity in the developing cerebral cortex. Most importantly, however, we were given the freedom to explore and design our own projects while at the same time developing a close relationship with Dr. Moody.

I am currently spending this year working in the laboratory of Dr. Ana BelÚn Elgoyhen in Buenos Aires, Argentina. Our research is focused on the a9a10 nicotinic acetylcholine receptor, which mediates neurotransmission between the brainstem and the outer hair cells of the cochlea. In doing so, this system protects the inner ear against acoustic trauma. In my current project, I use a variety of molecular and electrophysiological techniques to study the unique pharmacological profile and structure-function relationship of this receptor.

During my time here, I have greatly furthered my understanding of neuropharmacology and receptor dynamics. Further, however, this experience has afforded me the opportunity to become immersed in another culture and broaden my understanding of the world outside of Seattle. I have little doubt that the lessons I learn this year, both science and non-science related, will greatly serve me in the future as I pursue the fields of medicine and neuroscience. In closing, I would like to sincerely thank the Washington Research Foundation, without whose generous support this experience would not have been possible.

Mentor: William Moody, Biology

Project Title: Indentification and functional characterization of the allosteric binding site for calcium ions in the a9a10 nicotinic acetylcholine receptor

Abstract: The native receptor that mediates transmission between efferent olivocochlear neurons and outer hair cells of the cochlea is composed of the α9 and α10 cholinergic nicotinic subunits. This receptor differentiates itself from other members of the nicotinic acetylcholine (ACh) receptor family in multiple ways, arguably the most notable being its distinct pharmacological profile. While there have been many identified antagonists of this receptor, very few effective agonists have been characterized. However, in light of the proposed role of the efferent olivocochlear system in protection against acoustic damage, it is highly desirable that specific, efficacious agonists of the α9α10 receptor be identified. In this study, we have used molecular modeling of the α9α10 receptor in order to design a series of ACh analogs, which we subsequently tested for action against the α9α10 receptor expressed in Xenopus laevis oocytes. Preliminary results have been extremely promising. The first generation of compounds that we tested included two members that, while displaying EC50 values orders of magnitude lower than that of ACh, managed to more efficaciously activate currents through the receptor. A second generation was subsequently developed, and one compound was identified that had an EC50 value significantly lower than that of ACh, while displaying an efficacy statistically indistinguishable from that of the native transmitter. Based on these early results, we are striving to design a series of agonists that combine the improved efficacy and affinity observed by these different lead compounds. Subsequently, we plan to investigate the specificity of our improved agonist by testing it for action in the α7 and α4β2 neuronal nicotinic ACh receptors. We hope that the work we are currently performing could someday provide the basis for the development of a novel drug that could be used in the protection against acoustic trauma.