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

描述(申请人提供)：这项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。多巴胺信号参与学习和记忆，异常的多巴胺信号与多种精神障碍有关，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，但我们对多巴胺起作用的信号机制还没有清楚的了解。我已经开发了一种遗传策略来识别以线虫为模型的多巴胺信号通路的生理成分。在线虫和人类之间，多巴胺信号传递机制是保守的。我的具体目标是：1)进行遗传筛选，以分离在多巴胺信号转导方面有缺陷的突变体，并使用成熟的行为分析对突变体进行表型分析；2)克隆突变体识别的信号基因，并从分子上分析它们在多巴胺信号转导中的功能。基因分析有可能识别信号成分，根据分析的性质，这些成分必须具有生理相关性。这种遗传策略不同于以前用来识别多巴胺信号成分的其他策略。通过这一分析确定的新的信号分子将代表开发新的治疗策略的新靶点，以治疗与多巴胺信号缺陷相关的精神障碍。

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.