Genetic Dissection of Serotonergic Phenotypes in C. elegans

描述（由申请人提供）：在脊椎动物和无脊椎动物中，5-羟色胺（5-HT）信号传导调节大量的行为和生理过程。5 HT表型复杂性的遗传基础和分子机制还不清楚。因此，阐明基因和分子机制，调节5 HT神经元的发育和功能，将提供深入了解神经元多样性的原则，并揭示在分子和细胞水平上的神经系统和生理学的相互影响。利用复杂的C. elegans遗传学，我们独特的突变体和分子标记，允许在活动物的单细胞分辨率下定量测量5 HT的产生，我们正在进行5 HT系统的遗传解剖，测试一个中心假设：不同神经元中5-HT的产生受不同转录因子的调节，并通过不同的机制响应于不同的内外环境刺激，以促进5-HT的产生。不同的生理功能。这项建议有四个具体目标。(1)通过对我们收集的突变体进行遗传作图和RNA干扰筛选，我们将确定新的基因，这些基因指定5 HT的身份并调节已识别神经元中的5 HT产生。(2)使用抑制遗传学，我们将遵循我们的发现，即一对5 HT神经元感觉末端的TRP通道通过定义与通道相互作用并作用于通道下游的成分来控制5 HT的产生。(3)使用分子，细胞和行为的方法，我们将组织这样确定的基因进入分子和细胞途径。(4)使用我们建立的范例，我们将测试是否在特定的5 HT神经元的特定信号级联调节特定的行为，如果他们控制不同的应激反应途径。靶向5 HT系统的药物是治疗抑郁症和许多行为和神经精神障碍的最常用处方疗法。在模式生物中鉴定调节5 HT信号传导的基因和生化途径将导致在与疾病的关联研究中测试引人注目的新候选物，可能导致新的诊断和新的药物。

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.