Analysis of tyraminergic signaling in Caenorhabditis elegans

秀丽隐杆线虫酪胺能信号传导分析

基本信息

批准号：
8214652
负责人：
Mark Alkema
金额：
$ 32.25万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-05-01 至 2014-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8214652
关键词：
Acetylcholine Affect Amines Animal Behavior Attention Behavior Behavior Control Behavioral Biochemical Biogenic Amines Biological Models Brain Caenorhabditis elegans Cells Chemicals Complex Control Animal Coupled Couples Defect Diet Disease Drug Addiction Drug abuse Event G-Protein-Coupled Receptors GTP-Binding Proteins Genes Genetic Genetic Screening Genome Goals Head Head Movements Headache Health Human Ion Channel Knowledge Laboratories Lasers Light Link Locomotion Maps Measures Membrane Mental Depression Microsurgery Migraine Modeling Molecular Molecular Profiling Monoamine Oxidase Inhibitors Motor Neurons Muscle Mutation Nematoda Nervous system structure Neuromuscular Junction Neurons Neurotransmitters Organism Output Paralysed Parkinson Disease Patch-Clamp Techniques Pathway interactions Pattern Pharmaceutical Preparations Physiology Prevention Property Proteins Reaction Resistance Role Schizophrenia Signal Pathway Signal Transduction Synapses Synaptic Transmission System Techniques Time Touch sensation Tyramine Xenopus oocyte base direct application egg gene cloning genetic analysis human CCR10 protein human disease in vivo insight interest mutant nervous system disorder neural circuit neuroregulation novel positional cloning postsynaptic prevent promoter receptor receptor function relating to nervous system research study response synaptic function tyramine receptor

项目摘要

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.

描述（由申请人提供）：痕量胺，酪胺，与各种人类神经系统疾病有关，包括抑郁症，偏头痛，精神分裂症和药物滥用。尽管酪胺在中枢神经系统中的作用知之甚少，但哺乳动物G蛋白偶联受体的最近表征可以被酪胺激活，这引起了人们对酪胺在人类生理学和疾病中的作用的新兴趣。该提案的长期目标是了解酪胺在分子，细胞和神经回路水平上如何运行以控制行为。为此，将在线虫秀丽隐杆线虫的简单神经系统中分析酪氨酸能信号传导的机制。我们的分析确定，秀丽隐杆线虫具有独特的硫蛋白能细胞，酪胺可以调节几种行为。该项目将结合药理，遗传和电生理技术来了解酪胺功能。分析SHO-1的药理和表达谱的分析，SHO-1是一种在我们实验室中分离出的新型离子酪氨酸受体，将提供有关它如何调节不同神经回路输出的洞察力。 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的突变体的行为分析应揭示离子型和代谢性途径如何协同控制依赖蛋白酪胺的行为。神经肌肉连接处酪胺突触传播的电生理分析应确定酪胺如何影响突触后特性。最后，将进行无偏的遗传筛选，以寻找对外源性酪氨酸抗性的突变体。这种突变体的表征应鉴定出新的信号传导成分，并阐明酪胺受体下游的信号事件。这些实验将提供有关酪胺如何改变神经回路和控制动物行为的多层次观点。鉴于酪胺与神经系统疾病的联系，这些研究最终应加速我们对人类生理和疾病中酪胺功能的理解。公共卫生相关性：尽管大脑化学物质（酪胺）与各种各样的神经系统疾病有关，包括药物成瘾，抑郁症，注意力缺陷障碍，帕金森氏病，精神分裂症和头痛，但对其功能知之甚少。由于我们对人类疾病的大部分理解都来自对诸如圆形蠕虫（Caenorhabditis elegrans）等简单生物的研究，因此我们建议研究酪胺如何控制该动物在分子和细胞水平上的行为。我们的研究将更好地了解酪胺在大脑中的功能作用，这是治疗和预防人类神经系统疾病的最终目标。