Targeted Mutations to Study Anesthetic Mechanisms

描述：(由申请人提供)这份为期五年的职业发展提案的目标是为首席调查员Dev Chandra， 有机会发展成为一名独立的研究人员和胜任的 牙科麻醉学领域的临床医生。私家侦探将参加培训 这将使该大学神经科学中心的博士学位达到顶峰 匹兹堡大学。他的研究培训将在 Gregg Homanics实验室，博士，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。 虽然麻醉的发现彻底改变了牙科和 药物治疗，目前尚不清楚麻醉剂是如何引起临床的 以可逆的方式产生影响。了解这些机制最终将 导致更安全和更有效的麻醉治疗的发展 医疗模式。基因敲除小鼠彻底改变了对基因敲除的研究 单个蛋白质在麻醉药作用中的作用 整个动物。使用条件基因对这种方法进行了进一步的改进 一种仅在某些情况下允许基因失活的基因敲除技术 细胞或在特定的发育时期。 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组成部分。这 研究建议调查不同亚基对基因的贡献 GABAA-R具有全局或区域改变表达模式的小鼠模型 将使用电池创建和分析Gamma2或Alpha4亚基的 分子、细胞和行为分析。这些研究将阐明 γ-2或α-4亚单位在临床相关行为诱导中的作用 通过中枢作用的麻醉剂。

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.