MOLECULAR BIOLOGY OF BASAL GANGLIA SPECIFIC PHOSPHOPROTEINS

基底节特异性磷酸蛋白的分子生物学

• 批准号: 6111333
• 负责人: PAUL GREENGARD
• 金额: $ 30.36万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-07-01 至 2000-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6111333
• 关键词: active sites; antisense nucleic acid; basal ganglia; biological signal transduction; cell line; corpus striatum; dopamine; dopamine receptor; electrophysiology; enzyme complex; enzyme substrate; gene deletion mutation; gene targeting; genetically modified animals; glutamates; laboratory mouse; neural transmission; phosphatase inhibitor; phosphoprotein phosphatase; phosphoproteins; phosphorylation; protein kinase; protein structure function; sodium potassium exchanging ATPase; tissue /cell culture

The major objective of this application is to seek an understanding of the-intracellular signalling mechanisms by which dopamine exerts its effects in striatal neurons in the basal ganglia. This includes an understanding not only of the intracellular messengers that mediate the dopaminergic signal but also an understanding of how this signal is integrated together with that of a variety of other neurotransmitters impinging on striatal neurons. A major goal of the proposed studies is to generate, by novel technologies, genetically altered animals that will serve as models in which to study dopamine signalling pathways. These studies will allow the characterization of the involvement of individual components of the dopaminergic signalling pathways without the use of non-specific inhibitors. In addition, it also allows the analysis of the effect of these mutations in whole animals in which the complexity of interacting neurotransmitter pathways is preserved in the basal ganglia as well as other brain regions. Additional goals of the proposed studies are to use recently introduced molecular biological techniques to identify novel components of the dopamine signalling pathways. Specifically the yeast two-hybrid technique will be used to isolate proteins that interact with the phosphoproteins or with the enzymes that regulate their phosphorylation and dephosphorylation. These studies will be of particular importance in understanding such diseases as Parkinson's disease and schizophrenia which result in part from defects in dopamine- signalling pathways. In addition, the availability of mouse models in which specific components of dopamine-signalling pathways are deficient may be useful in the development of new therapeutic strategies for the treatment of such diseases.

本申请的主要目的是寻求理解 多巴胺发挥其作用的细胞内信号传导机制 对基底神经节纹状体神经元的影响。这包括 不仅了解细胞内的信使， 多巴胺能信号，但也了解这个信号是如何 与其他多种神经递质结合在一起 撞击纹状体神经元拟议研究的一个主要目标是 通过新的技术，产生转基因动物， 作为研究多巴胺信号通路的模型。这些 研究将允许描述个人参与的特征 多巴胺能信号通路的组分，而不使用 非特异性抑制剂。此外，它还允许分析 这些突变在整个动物中的影响， 相互作用的神经递质通路保留在基底神经节中 以及其他大脑区域。拟议研究的其他目标 是利用最近引进的分子生物学技术， 识别多巴胺信号通路的新成分。 具体来说，酵母双杂交技术将用于分离 蛋白质与磷蛋白或酶相互作用， 调节它们的磷酸化和去磷酸化。这些研究将 对于理解帕金森氏症等疾病 疾病和精神分裂症，部分原因是多巴胺的缺陷， 信号通路此外，小鼠模型的可用性， 多巴胺信号通路的哪些特定成分缺乏 可能有助于开发新的治疗策略， 治疗这些疾病。