METABOTROPIC GLUTAMATE RECEPTOR EXPRESSION AND FUNCTION

代谢型谷氨酸受体的表达和功能

• 批准号: 2259820
• 负责人: JARDA T WROBLEWSKI
• 金额: $ 6.75万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-04-01 至 1999-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2259820
• 关键词: G protein; antisense nucleic acid; brain metabolism; calcium flux; cerebellum; complementary DNA; cyclic AMP; diacylglycerols; enzyme activity; excitatory aminoacid; glutamate receptor; granule cell; inositol phosphates; laboratory rabbit; laboratory rat; lipid metabolism; neuropharmacology; nucleic acid probes; nucleic acid sequence; phosphatidylinositols; phospholipase C; protein structure function; receptor coupling; receptor expression; tissue /cell culture

I am currently an Associate Professor (tenure-track) in the department of Pharmacology at Georgetown University and hold a joint appointment in the Fidia-Georgetown Institute for the Neurosciences. My long-term research goal is to understand the role of G-protein coupled metabotropic glutamate receptors in neuronal function. My career goal is to establish a strong research program and gain expertise and knowledge allowing me to combine the techniques of neurochemistry, pharmacology, cell biology and molecular biology to study receptor functional expression and intracellular signalling. I obtained my Ph.D. from the Department of Neurochemistry, Polish Academy of Sciences in Warsaw in 1979. My postdoctoral training in neuropharmacology was with Dr. E. Costa at NIMH. I joined the faculty at Georgetown University in 1985 and have established at FGIN, under the direction of Dr. E. Costa, a research program in the field of pharmacology and signal transduction of excitatory amino acid receptors. This work has been the basis for my participation in the Program Project "Excitatory Amino Acids: Role in CNS Disorders" (P01-NS28130, R. A. Gillis, Program Director) for 3 years as a Core Director, and since 1993 as a principal investigator of one of the projects which has been funded through 3/31/98. The current RCDA application is submitted to enable me to expand my expertise in neurosciences and to devote additional time to my research program. By minimizing my teaching and administrative responsabilities, the award will allow for personal growth at several levels and for in-depth training in molecular biology an antibody preparation techniques. The research plan (based on the funded Program Project grant) focuses on the expression and function of metabotropic glutamate receptors (mGluRs) in primary cultures of neurons. The specific aims are: to evaluate the functional expression of mGluRTs coupled to phosphoinositide (PI) hydrolysis by determining the developmental pattern of expression of mRNA, receptor protein, and of the appearance of the PI response in neurons cultured in media enhancing receptor expression and by establishing the agonist and antagonist pharmacology of these receptors; to determine the role of mGluRs in PI metabolism by identifying the specific substrates and products of phospholipase C coupled to mGluRs; to determine the role of PI- coupled mGluRs in intracellular calcium homeostasis; and to determine the role of ionotropic glutamate receptors (NMDA and AMPA) interacting with mGluRs in the regulation of PI hydrolysis. An important goal of the current RCDA application is to extend the proposed studies to the entire family of mGluRs, including those negatively coupled to adenylate cyclase. Thus, I propose to study the expression of mRNA and receptor protein for all PI and cAMP-coupled mGluRs in primary neuronal cultures and to establish the selective pharmacology of the receptor-induced responses. These studies will provide information fundamental for the understanding of the pharmacological and neurochemical properties of mGluRs, their role in neuronal function, and for development of future therapeutic strategies.

我目前是一名副教授（终身教职）在系 药理学在乔治敦大学，并举行了联合任命， Fidia-Georgetown神经科学研究所 我的长期研究 目标是了解G蛋白偶联代谢型谷氨酸的作用 神经元功能中的受体。 我的职业目标是建立一个强大的 研究计划，并获得专业知识和知识，使我能够联合收割机 神经化学、药理学、细胞生物学和分子生物学技术 研究受体功能表达和细胞内 信号装置. 我获得了博士学位。来自波兰科学院神经化学系 1979年在华沙举行的科学会议上。 我的博士后训练 神经药理学是和E医生一起做的NIMH的科斯塔。 我加入了 乔治敦大学于1985年成立，并在FGIN，根据 博士的方向。Costa是药理学领域的一个研究项目， 和兴奋性氨基酸受体的信号转导。 这项工作 是我参与"令人兴奋的"项目的基础。 氨基酸：在中枢神经系统疾病中的作用"（P01-NS28130，R. a.吉利斯，程序 自1993年起担任校长，担任核心主任3年 1998年3月31日资助的一个项目的调查员。 目前的RCDA申请提交，使我能够扩大我的 在神经科学方面的专业知识，并投入更多的时间在我的研究 程序. 通过减少我的教学和行政责任， 该奖项将允许在多个层面上的个人成长和深入 分子生物学和抗体制备技术培训。 研究计划（基于资助的计划项目赠款）的重点是 代谢型谷氨酸受体（mGluRs）在脑内的表达和功能 神经元的原代培养物。 具体目标是： 与磷酸肌醇（PI）偶联的mGluRTs的功能性表达 通过确定mRNA表达的发育模式进行水解， 受体蛋白，以及神经元中PI反应的出现 在培养基中培养增强受体表达，并通过建立 这些受体的激动剂和拮抗剂药理学;以确定 mGluRs在PI代谢中的作用，通过鉴定特异性底物， 磷脂酶C与mGluRs偶联的产物;以确定PI-1的作用。 偶联的mGluRs在细胞内钙稳态中的作用;并确定 离子型谷氨酸受体（NMDA和AMPA）与 mGluRs在PI水解调节中的作用。 的重要目标 目前RCDA的应用是将拟议的研究扩展到整个 mGluR家族，包括与腺苷酸环化酶负偶联的那些。 因此，我建议研究mRNA和受体蛋白的表达， 原代神经元培养物中所有PI和cAMP偶联的mGluR， 建立受体诱导反应的选择性药理学。 这些研究将为理解 mGluRs的药理学和神经化学性质，它们在 神经元功能，以及未来治疗策略的发展。