PHARMACOLOGICAL REGULATION OF BASAL GANGLIA ENRICHED PHOSPHOPROTEIN

基底节富含磷酸蛋白的药理调节

• 批准号: 6242978
• 负责人: GRETCHEN L SNYDER
• 金额: $ 28.07万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-07-01 至 1998-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6242978
• 关键词: basal ganglia; biological signal transduction; casein kinase; cell line; dopamine; enzyme activity; gene targeting; genetically modified animals; human tissue; laboratory mouse; laboratory rat; phosphatase inhibitor; phosphoprotein phosphatase; phosphoproteins; phosphorylation; postmortem; protein kinase; psychopharmacology; schizophrenia; tissue /cell culture

This project will seek to examine protein phosphorylation pathways in the basal ganglia which mediate the actions of dopamine in normal and abnormal brain function. The pharmacological regulation of phosphoproteins enriched in the basal ganglia will be studied using intact cell preparations derived from basal ganglia structures of normal animals (e.g., neostriatal slices, primary neostriatal cell cultures, synaptosomes) or in immortalized cells which mimic various physiological properties of basal ganglia neurons. In addition, the regulation of these phosphoproteins under physiological conditions will be studied by administration of drugs to normal, intact animals and the subsequent analysis of the phosphorylated proteins in the brains of these animals. The goal of these studies is to identify first messenger and signal transduction pathways which play a significant role in regulating the function of basal ganglia phosphoproteins in the intact animal. Some of these studies will seek to identify signaling pathways which regulate phosphoproteins by using transgenic animals, which express mutagenized phosphoproteins, or genetically-altered animals, which are deficient in cell signaling molecules. Finally, the levels of phosphoproteins and associated signaling molecules will be measured in post-mortem brain tissue from normal individuals and patients with schizophrenia, in order to assess the possible involvement of phosphoproteins and their regulatory pathways in this dopamine-associated brain disorder. It is anticipated that these studies will provide an essential understanding of dopamine-mediated protein phosphorylation in the normal brain and the possible role of this process in dopamine-mediated motor and psychiatric disease.

该项目将寻求检查蛋白质磷酸化途径 基底神经节在正常和正常情况下介导多巴胺的作用 大脑功能异常。药理调节 将使用以下方法研究基底神经节中富集的磷蛋白 源自正常基底神经节结构的完整细胞制剂 动物（例如，新纹状体切片、原代新纹状体细胞培养物、 突触体）或模拟各种生理的永生化细胞 基底节神经元的特性。此外，这些规定的监管 生理条件下的磷蛋白将被研究 对正常、完整的动物施用药物以及随后的 分析这些动物大脑中的磷酸化蛋白质。 这些研究的目标是确定第一个信使和信号 转导途径在调节中起重要作用 完整动物中基底神经节磷蛋白的功能。一些 这些研究将寻求确定调节的信号通路 通过使用转基因动物来表达诱变的磷蛋白 磷蛋白，或基因改变的动物，缺乏 细胞信号分子。最后，磷蛋白和磷蛋白的水平 相关信号分子将在死后大脑中进行测量 正常人和精神分裂症患者的组织，按顺序 评估磷蛋白及其可能的参与 这种多巴胺相关脑部疾病的调节途径。这是 预计这些研究将提供重要的理解 正常大脑中多巴胺介导的蛋白质磷酸化和 该过程在多巴胺介导的运动和精神疾病中的可能作用 疾病。