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Functional genomics of dopamine neurons

多巴胺神经元的功能基因组学

基本信息

批准号：
9226588
负责人：
Niels Ringstad
金额：
$ 25.43万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-15 至 2018-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9226588
关键词：
Address Affect Animal Model Animals Axon Behavior Behavioral Brain Caenorhabditis elegans Calcium Candidate Disease Gene Cell physiology Cells Defect Dendrites Detection Development Dopamine Dopamine Receptor Enzymes Felis catus Food Gene Expression Gene Mutation Genes Genetic Genetic Epistasis Genetic study Goals Human Human Genome Image Invertebrates Link Locomotion Measures Mediating Mental disorders Methods Modeling Molecular Molecular Genetics Monitor Morphogenesis Movement Disorders Mutate Nematoda Neurobiology Neuromodulator Neurons Parkinson Disease Phenocopy Physiology Play Process Receptor Gene Rewards Role Schizophrenia Signal Pathway Signal Transduction Stereotyped Behavior Stereotyping Structure Synapses Testing Transcript Vision abstracting addiction base cell type dopamine transporter dopaminergic neuron driving behavior drug of abuse functional genomics gene function genetic analysis in vivo knock-down live cell imaging loss of function molecular targeted therapies mutant nervous system disorder neuropsychiatric disorder new therapeutic target novel novel therapeutics optogenetics receptor relating to nervous system research study response reuptake screening synaptogenesis therapeutic target

项目摘要

PROJECT SUMMARY The neuromodulator dopamine is important for many brain functions: loss of dopamine neurons causes movement disorders, such as Parkinson's disease; dopamine signaling is targeted by drugs of abuse and integral to the neurobiology of reward and addiction; and dopamine signaling is a therapeutic target for the treatment of many neuropsychiatric disorders. Despite its importance in the brain, relatively little is known about mechanisms that regulate dopamine release in vivo or are otherwise required for the function of dopamine neurons. To directly address this question, we have used a simple invertebrate model – the nematode C. elegans - to identify molecules required in vivo for dopamine signaling. We have identified genes whose expression is highly enriched in dopamine neurons, and by testing the corresponding mutants for defects in a behavior that requires endogenous dopamine we have identified five evolutionarily conserved genes that are likely required for the function of dopamine neurons. Using live-cell imaging and studies of dopamine neuron physiology we will determine the function of these genes. We will also use genetic analyses to determine how these genes interact with known components of dopamine signaling pathways. We expect that these studies will identify new therapeutic targets for the treatment of neurological and psychiatric disorders. Importantly, because extant therapeutic targets act downstream of dopamine release (they are receptors, transporters and dopamine-degrading enzymes), we also anticipate that our studies will identify targets with fundamentally new mechanisms of action in dopamine signaling.

项目摘要神经调节剂多巴胺对许多大脑功能都很重要：多巴胺神经元的丧失会导致运动障碍，如帕金森病;多巴胺信号是滥用药物的目标并且是奖赏和成瘾的神经生物学的组成部分;多巴胺信号是治疗靶点用于治疗许多神经精神疾病。尽管它在大脑中很重要，已知调节体内多巴胺释放的机制，或者是多巴胺神经元的功能。为了直接回答这个问题，我们使用了一种简单的无脊椎动物，模式线虫C. elegans -识别体内多巴胺信号传导所需的分子。我们已经确定了在多巴胺神经元中高度富集表达的基因，并通过测试我们已经鉴定出了需要内源性多巴胺的行为缺陷的相应突变体五个进化上保守的基因，可能是多巴胺神经元功能所必需的。使用活细胞成像和多巴胺神经元生理学的研究，我们将确定这些功能，基因.我们还将使用遗传分析来确定这些基因如何与已知的基因相互作用。多巴胺信号通路的组成部分。我们希望这些研究将发现新的治疗方法，用于治疗神经和精神疾病的靶点。重要的是，因为现存的治疗靶点作用于多巴胺释放的下游（它们是受体、转运蛋白和多巴胺降解酶），我们还预计，我们的研究将确定目标与多巴胺信号传导的全新作用机制。