Genetic Dissection of Serotonergic Phenotypes in C. elegans

线虫血清素能表型的遗传解剖

• 批准号: 7845079
• 负责人: JI Y SZE
• 金额: $ 35.28万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-08-01 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7845079
• 关键词: Affect; Animal Model; Animals; Autistic Disorder; Behavior; Behavior Control; Behavioral; Behavioral Assay; Biochemical Pathway; Caenorhabditis elegans; Cells; Chromosome Mapping; Clinic; Complex; Deletion Mutation; Development; Disease; Dissection; Down-Regulation; Drug Delivery Systems; Endogenous depression; Energy Metabolism; Enzymes; Epitopes; Genes; Genetic; Genetic Markers; Genetic Programming; Goals; Grant; Insulin Receptor; Invertebrates; Lead; Life; Link; Maps; Measures; Mental Depression; Molecular; Monitor; Mutagenesis; Mutation; Nervous System Physiology; Neurons; Neurotransmitters; Non-Insulin-Dependent Diabetes Mellitus; Organism; Pathway interactions; Pharmaceutical Preparations; Phenotype; Physiological; Physiological Processes; Point Mutation; Polygenic Traits; Production; RNA Interference; Receptor Signaling; Research; Research Personnel; Resistance; Resolution; Role; Schizophrenia; Sensory; Serotonin; Signal Transduction; Single Nucleotide Polymorphism Map; Specific qualifier value; Specificity; Stimulus; Stress; Synaptic Transmission; System; TRP channel; Testing; Therapeutic; Therapeutic Agents; Transcriptional Regulation; Tryptophan 5-monooxygenase; Vertebrates; base; gain of function; insight; molecular marker; mutant; neuropsychiatry; novel diagnostics; positional cloning; programs; promoter; receptor function; response; reuptake; tool; trait; transcription factor; vif Genes

DESCRIPTION (provided by applicant): In both vertebrates and invertebrates, serotonin (5HT) signaling regulates a vast array of behavior and physiological processes. The genetic basis and molecular mechanisms underlying the complexity of 5HT phenotypes are not well understood. Thus elucidation of genes and molecular mechanisms that regulate the development and function of 5HT neurons will provide insights into the principles of neuronal diversity and reveal reciprocal effects of the nervous system and physiology at molecular and cellular levels. Taking the advantage of sophisticated C. elegans genetics, our unique mutants, and molecular markers that allow a quantifiable measure of 5HT production at the resolution of single cells in living animals, we are undertaking genetic dissection of the 5HT system, testing a central hypothesis: 5HT production in different neurons is regulated by different transcription factors and is modulated by different mechanisms in response to different internal and external environmental stimuli to subserve different physiological functions. This proposal has four specific objectives. (1) By genetic mapping of our collected mutants and RNA-interference screens, we will define new genes that specify 5HT identity and that regulate 5HT production in identified neurons. (2) Using suppressor genetics, we will follow our discovery that a TRP channel at the sensory ending of a pair of 5HT neurons controls 5HT production by defining components that interact with and that act downstream of the channel. (3) Using molecular, cellular, and behavioral approaches, we will organize so identified genes into molecular and cellular pathways. (4) Using our established paradigms, we will test whether specific signaling cascades in specific 5HT neurons modulate specific behavior and if they control distinct stress responsive pathways. Drugs that target the 5HT system are the most commonly prescribed therapeutics for the treatment of depression and many behavioral and neuropsychiatric disorders. Identification of genes and biochemical pathways that regulate 5HT signaling in a model organism will lead to compelling new candidates to be tested in association studies with the diseases, potentially leading to novel diagnostics and new medications.

描述（由申请人提供）：在脊椎动物和无脊椎动物中，羟色胺（5HT）信号传导调节了大量的行为和生理过程。 5HT表型复杂性的遗传基础和分子机制尚不清楚。因此，调节5HT神经元的发育和功能的基因和分子机制的阐明将提供对神经元多样性原理的见解，并揭示神经系统和生理学在分子和细胞水平上的相互影响。利用复杂的秀丽隐杆线虫遗传学，我们的独特突变体和分子标记，可以在活动物中单个细胞的分辨率下可量化5HT产生的量度，我们正在对5HT系统进行遗传解剖，测试一个中心假设，从而通过不同的转录因素和不同的内部机制来调节不同神经元的5HT产生的中心假设，并且由不同的内在机构进行了不同的调节，并且是不同的机制，并且是不同的机制。功能。该提案有四个特定目标。 （1）通过我们收集的突变体和RNA解关筛选的遗传学映射，我们将定义指定5HT同一性并调节已鉴定神经元中5HT产生的新基因。 （2）使用抑制器遗传学，我们将发现发现，在一对5HT神经元的感觉结束处的TRP通道通过定义与通道下游相互作用的组件来控制5HT的产生。 （3）使用分子，细胞和行为方法，我们将其组织为分子和细胞途径。 （4）使用我们已建立的范式，我们将测试特定的5HT神经元中的特定信号级联反应是否调节特定的行为以及它们是否控制着不同的应力响应途径。针对5HT系统的药物是治疗抑郁症以及许多行为和神经精神疾病的最常见的治疗剂。在模型生物体中调节5HT信号传导的基因和生化途径的鉴定将导致在与疾病的关联研究中对新的候选者进行迫使新的候选者，这可能导致新的诊断和新药物。