2017 IARS Mentored Research Award

Wayland Cheng, MD, PhD

Research Fellow and Associate Faculty Member, Washington University in St. Louis

Dr. Cheng’s Research

The Structural Basis of Neurosteroid Binding to the GABA(A) Receptor

Neurosteroids are endogenous brain sterols that potently modulate GABA(A) receptors (GABAARs), and are being developed as anesthetics or treatments of neurologic and psychiatric disorders. Although neurosteroid modulation of the GABAAR has been well characterized, neurosteroid binding to the GABAAR is not well understood. A detailed understanding of the stoichiometry/site(s), orientation and pharmacology of neurosteroid binding to the GABAAR is essential for structure-based design of neurosteroid anesthetics. To address this deficiency, the candidate will apply photo-affinity labeling with an existing library of neurosteroid photolabeling reagents, and top-down mass spectrometry (MS), a technique that analyzes intact membrane proteins, to characterize neurosteroid photolabeling of the GABAAR. Aim 1 is to determine the stoichiometry/site(s) and orientation of neurosteroid photolabeling of ELIC-GABAAR chimeras (tractable model proteins where the transmembrane domain consists of GABAAR subunits), and aim 2 is to determine the stereoselectivity of neurosteroid photolabeling. This work will yield novel insights into the structural basis of neurosteroid binding to the GABAAR. It will also establish a generalizable method using top-down MS for characterizing small molecule photolabeling of membrane proteins, and is anticipated to lead to sustainable R01-level funding. This research will be conducted under the mentorship of Dr. Alex Evers, an expert in anesthetic pharmacology, photo-affinity labeling and mass spectrometry analysis of membrane proteins. The candidate will also be working closely with Dr. Michael Gross, a leader in top-down MS of membrane proteins at Washington University. The Anesthesiology Department at Washington University provides a robust environment for research in molecular pharmacology.

Encourage, stimulate, and fund ongoing anesthesia-related research projects that will enhance and advance the specialty, and to disseminate current, state-of-the-art, basic and clinical research data in all areas of clinical anesthesia, including perioperative medicine, critical care, and pain management. The IARS is focused solely on the advancement and support of education and scientific research related to anesthesiology.

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IMRA Awards

This award is intended to support investigations that will further the understanding of clinical practice in anesthesiology and related sciences. Up to four research projects are selected annually, with a maximum award of $175,000 each, payable over two years.

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