The goal of this five-year career development proposal is to provide the Principal Investigator, Dev Chandra, with the opportunity to develop into an independent researcher and competent Clinician in the field of dental anesthesiology. The PI will engage in training that will culminate in a Ph.D. degree from the Center for Neuroscience at the University of Pittsburgh. His research training will be conducted in the laboratory of Gregg Homanics, Ph.D., at the University of Pittsburgh in the Departments of Anesthesiology and Pharmacology. Clinical training in dental anesthesiology will be undertaken at the University of Pittsburgh School of Dental Medicine. While the discovery of anesthesia has revolutionized delivery of dental and medical treatment, it remains unknown how anesthetics induce their clinical effects in a reversible manner. Understanding these mechanisms will ultimately lead to the development of safer and more effective anesthetic treatment modalities. Gene knockout mice have revolutionized the investigation of the role of individual proteins in the action of anesthetics within the context of the whole animal. This approach has been further refined using conditional gene knockout technology which allows the inactivation of a gene only in certain cells or during specific developmental periods. The gamma-aminobutyric acid type A receptor (GABAA-R) has been extensively implicated as a key component of the mechanism of action of anesthetics. This study proposes to investigate the contribution of different subunits of the GABAA-R. Mouse models with globally or regionally altered expression patterns of the gamma2 or alpha4 subunits will be created and analyzed using a battery of molecular, cellular and behavioral assays. These studies will elucidate the role of the gamma2 or alpha4 subunits in clinically relevant behaviors induced by centrally acting anesthetics.
