Novel dopamine signaling mechanisms identified by genetic analysis in C. elegans.

描述（由申请人提供）：本提案的长期目标是了解神经递质多巴胺如何调节神经元的活动。多巴胺信号传导参与学习和记忆，并且异常的多巴胺信号传导已经涉及各种精神障碍，包括精神分裂症、药物成瘾、抑郁症和帕金森病。尽管了解多巴胺如何影响大脑功能很重要，但我们对多巴胺作用的信号机制并没有明确的了解。我已经开发了一种遗传策略，以确定多巴胺信号通路的生理成分，使用C。优雅的模特多巴胺信号转导机制在C. elegans优雅and humans人类.我的具体目标是：1）进行遗传筛选以分离多巴胺信号传导缺陷的突变体，并使用完善的行为测定法进行突变体的表型分析; 2）克隆由突变体鉴定的信号传导基因，并从分子上分析它们在多巴胺信号传导中的功能。遗传分析具有鉴定信号传导组分的潜力，根据分析的性质，这些信号传导组分必须具有生理相关性。这种遗传策略与以前用于识别多巴胺信号成分的其他策略不同。通过这种分析鉴定的新型信号分子将代表开发新的治疗策略以治疗与多巴胺信号传导缺陷相关的精神障碍的新靶点。

DESCRIPTION (provided by applicant): The long-term goal of this proposal is to understand how the neurotransmitter dopamine regulates the activities of neurons. Dopamine signaling is involved in learning and memory and abnormal dopamine signaling has been implicated in a variety of mental disorders including schizophrenia, drug addiction, depression, and Parkinson's disease. Despite the importance of understanding how dopamine affects brain function, we do not have a clear understanding of the signaling mechanisms by which dopamine acts. I have developed a genetic strategy to identify the physiological components of dopamine signaling pathways that uses C. elegans as a model. The mechanisms of dopamine signaling are conserved between C. elegans and humans. My specific aims are: 1) to perform a genetic screen to isolate mutants defective in dopamine signaling and to perform a phenotypic analysis of the mutants using well-established behavioral assays; 2) to clone the signaling genes identified by the mutants and to molecularly analyze their function in dopamine signaling. Genetic analysis has the potential to identify signaling components that, by the nature of the analysis, must be of physiological relevance. This genetic strategy is different than other strategies used previously to identify the components of dopamine signaling. Novel signaling molecules identified by this analysis would represent novel targets for the development of new therapeutic strategies to treat mental disorders associated with defects in dopamine signaling.