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

通过线虫遗传分析鉴定出新的多巴胺信号传导机制。

• 批准号: 7132443
• 负责人: DANIEL L CHASE
• 金额: $ 21.2万
• 依托单位: UNIVERSITY OF MASSACHUSETTS AMHERST
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-20 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7132443
• 关键词: Caenorhabditis elegans; behavior test; biological signal transduction; disease /disorder model; dopamine; gene expression; gene targeting; genetic screening; genetically modified animals; learning; memory; mutant; neuroregulation; phenotype; protein localization; protein structure function

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.

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。多巴胺信号与学习和记忆有关，多巴胺信号异常与多种精神疾病有关，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不清楚。我开发了一种遗传策略，以秀丽隐杆线虫为模型来识别多巴胺信号通路的生理成分。多巴胺信号传导机制在秀丽隐杆线虫和人类之间是保守的。我的具体目标是：1)进行基因筛选，以分离多巴胺信号缺陷突变体，并使用成熟的行为分析对突变体进行表型分析；2)克隆突变体所鉴定的信号基因，并对其在多巴胺信号传导中的功能进行分子分析。遗传分析具有识别信号成分的潜力，根据分析的性质，这些信号成分必须与生理相关。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。通过这一分析发现的新的信号分子将为开发新的治疗策略来治疗与多巴胺信号缺陷相关的精神障碍提供新的靶点。