PHARMACOLOGICAL REGULATION OF BASAL GANGLIA ENRICHED PHOSPHOPROTEIN

该项目将试图研究蛋白质的磷酸化途径。 基底节，介导正常和中枢多巴胺的活动 大脑功能异常。丹参的药理调节作用 富含在基底节的磷蛋白将用 取自正常人基底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、 突触体)或在模仿各种生理功能的永生化细胞中 基底节神经元的特性。此外，对这些的监管 生理条件下的磷蛋白将通过 给正常的、完整的动物和随后的 对这些动物大脑中的磷酸化蛋白质进行分析。 这些研究的目标是识别第一信使和信号 在调节细胞周期中起重要作用的信号转导通路 基底节磷蛋白在完整动物体内的功能。其中一些 这些研究将试图找出调节 利用表达诱变的转基因动物的磷蛋白 磷蛋白，或基因改变的动物，它们在 细胞信号分子。最后，磷蛋白水平和 相关的信号分子将在尸检的大脑中被测量 来自正常人和精神分裂症患者的组织，按顺序 以评估磷蛋白及其受体的可能参与 在这种与多巴胺相关的大脑紊乱中的调控途径。它是 预计这些研究将提供基本的理解 多巴胺介导的蛋白质磷酸化在正常大脑和 这一过程在多巴胺介导的运动和精神疾病中的可能作用 疾病。

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.