Analysis of tyraminergic signaling in Caenorhabditis elegans

描述(申请人提供)：示踪胺，酪胺，已涉及多种人类神经疾病，包括抑郁症，偏头痛，精神分裂症和药物滥用。虽然酪胺在中枢神经系统中的作用还知之甚少，但最近对酪胺激活的哺乳动物G蛋白偶联受体的研究引起了人们对酪胺在人类生理和疾病中的作用的新兴趣。这项建议的长期目标是了解酪胺如何在分子、细胞和神经电路水平上控制行为。为此，将在线虫的简单神经系统中分析酪胺能信号的机制。我们的分析已经确定线虫有不同的酪胺能细胞，而且酪胺调节着几种行为。这个项目将结合药理学、遗传学和电生理学技术来了解酪胺的功能。分析SHO-1的药理和表达谱，将为我们深入了解它如何调节不同神经回路的输出。对sho-1突变体的行为分析，以及G蛋白偶联酪胺受体Ser-2和Tyra-2突变体的行为分析，应该可以揭示电离和代谢性通路如何协调控制酪胺依赖行为。对神经肌肉接头处酪胺突触传递的电生理学分析应该确定酪胺如何影响突触后特性。最后，将进行无偏见的遗传筛选，以寻找对外源酪胺具有抗性的突变体。这些突变体的特征应该识别新的信号成分，并阐明酪胺受体下游的信号事件。这些实验将为酪胺如何改变神经回路的输出和控制动物行为提供多层次的视角。鉴于酪胺与神经疾病的联系，这些研究最终应该会加速我们对酪胺在人类生理和疾病中的作用的理解。与公共健康相关：尽管大脑化学物质酪胺与多种神经疾病有关，包括药物成瘾、抑郁症、注意力缺陷障碍、帕金森氏症、精神分裂症和头痛，但人们对其功能知之甚少。由于我们对人类疾病的大部分了解都来自于对圆线虫等简单生物体的研究，我们建议在分子和细胞水平上研究酪胺如何控制这种动物的行为。我们的研究将更好地了解酪胺在大脑中的功能作用，最终目标是治疗和预防人类神经疾病。

DESCRIPTION (provided by applicant): The trace amine, tyramine, has been implicated in a variety of human neurological disorders, including depression, migraine, schizophrenia and drug abuse. Although the role of tyramine in the CNS is poorly understood, the recent characterization of mammalian G-protein coupled receptors that can be activated by tyramine has aroused new interest in the role of tyramine in human physiology and disease. The long-term objective of this proposal is to understand how tyramine operates at the molecular, cellular, and neural circuit level to control behaviors. To this end, mechanisms of tyraminergic signaling will be analyzed in the simple nervous system of the nematode Caenorhabditis elegans. Our analysis has established that C. elegans has distinct tyraminergic cells and that tyramine regulates several behaviors. This project will use a combination of pharmacological, genetic, and electrophysiological techniques to understand tyramine function. Analysis of the pharmacological and expression profile of SHO-1, a novel ionotropic tyramine receptor isolated in our laboratory, will provide insight into how it modulates the output of distinct neural circuits. Behavioral analysis of sho-1 mutants, together with that of mutants for the G-protein coupled tyramine receptors ser-2 and tyra-2, should reveal how ionotropic and metabotropic pathways coordinately control tyramine dependent behaviors. Electrophysiological analysis of tyramine synaptic transmission at the neuromuscular junction should establish how tyramine affects postsynaptic properties. Lastly, an unbiased genetic screen will be conducted to search for mutants resistant to exogenous tyramine. Characterization of such mutants should identify novel signaling components and elucidate the signaling events downstream of tyramine receptors. These experiments will provide a multi-level perspective on how tyramine changes the output of neural circuits and controls animal behavior. Given tyramine's link with neurological disorders, these studies should ultimately accelerate our understanding of tyramine function in human physiology and disease. PUBLIC HEALTH RELEVANCE: Although the brain chemical, tyramine, is linked to a large variety of neurological disorders, including drug addiction, depression, attention hyper deficit disorders, Parkinson's disease, schizophrenia and headaches, little is known about its function. Since much of our understanding in human disease has come from studies of simple organisms like the round worm, Caenorhabditis elegans, we propose to study how tyramine controls behavior of this animal at the molecular and cellular level. Our studies will provide a better understanding of the functional role of tyramine in the brain, with the ultimate goal of treatment and prevention of human neurological disorders.