MOLECULAR BIOLOGY OF BASAL GANGLIA SPECIFIC PHOSPHOPROTEINS

本申请的主要目的是寻求对 多巴胺在细胞内发挥作用的信号机制 对纹状体基底节神经元的影响。这包括一个 了解不仅是细胞内的信使，它调节 多巴胺能信号，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 研究将允许刻画个人参与的特征 多巴胺能信号通路的组成部分而不使用 非特异性抑制剂。此外，它还允许分析 这些突变对整个动物的影响，其中复杂的 相互作用的神经递质通路保留在基底节 以及其他大脑区域。拟议研究的其他目标 是使用最近引进的分子生物学技术来 识别多巴胺信号通路的新成分。 具体地说，将使用酵母双杂交技术来分离 与磷蛋白或与酶相互作用的蛋白质 调节它们的磷酸化和去磷酸化。这些研究将 对了解像帕金森氏症这样的疾病特别重要 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，中提供的鼠标模型 多巴胺信号通路的哪些特定成分存在缺陷 可能有助于开发新的治疗策略 这类疾病的治疗。

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.