Targeted Mutations to Study Anesthetic Mechanisms

描述：（由申请人提供）这五年职业生涯的目标 发展建议是提供首席研究员，开发钱德拉， 有机会发展成为一名独立的研究人员和有能力的 牙科麻醉领域的临床医生。PI将参与培训 最终获得博士学位神经科学中心（Center for Neuroscience） 匹兹堡大学。他的研究培训将在 实验室Gregg Homanics博士，在匹兹堡大学， 麻醉学和药理学系。牙科临床培训 麻醉学将在匹兹堡大学医学院进行， 牙科医学。 虽然麻醉的发现已经彻底改变了牙科和 药物治疗，仍然不知道麻醉剂如何诱导其临床 以可逆的方式影响。了解这些机制将最终 导致更安全和更有效的麻醉治疗的发展 方式。基因敲除小鼠彻底改变了对 单个蛋白质在麻醉剂作用中的作用 整个动物。这种方法已被进一步完善，使用条件基因 基因敲除技术，它只允许在某些特定的基因中失活。 细胞或特定发育时期。 γ-氨基丁酸A型受体（GABAA-R）已被广泛研究， 被认为是麻醉剂作用机制的关键成分。这 研究建议调查不同亚基的贡献， 加巴河具有全局或区域改变的表达模式的小鼠模型 的γ 2或α 4亚基将被创建并使用电池进行分析 分子、细胞和行为分析。这些研究将阐明 γ 2或α 4亚单位在诱导的临床相关行为中的作用 通过中枢作用麻醉剂。

DESCRIPTION: (provided by applicant) 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.