Project 1 Genetic Networks Establishing Serontonergic Neuronal Idenity

改变的5 HT信号传导已经涉及许多神经系统疾病的发病机制， 精神疾病这些疾病中的许多是神经发育的起源和风险，为获得他们 可能受多种遗传易感因素的影响。项目1：基因网络 在建立5-羟色胺能神经元身份的基础上，Evan Deneris假设这些易感性中的一些可能是由于 因子可能是控制5 HT神经元发育的基因的等位基因变体，并且这些等位基因可能 通过不利地增加或减少5-HT系统活性而导致行为发病机制。虽然 一些SERT变异是精神健康障碍的可识别风险因素，大多数基因涉及 尚未研究5 HT神经元发育是否存在疾病相关等位基因。 在这一领域尚未取得进展，因为5 HT神经元难以进入分子水平。 基因研究。因此，只有少数基因组成的5 HT神经元发育， 方案已经确定。阻碍进展的另一个关键因素是， 研究5-HT神经元发育控制的功能需要方法学和专业知识 基因. Deneris开发了基于转基因的工具，可以直接和高度特异性地获得 胚胎和成体5 HT神经元。这里提出的研究将利用这些工具， 询问5 HT神经元转录组，从而鉴定可能控制5 HT神经元的基因 发展和功能。他提出的目标将解决以下问题： 在胚胎和出生后5 HT神经元发育的关键阶段表达？有哪些 头端和尾端5-HT神经元表达基因网络的差异？是不同阶段的 5 HT神经元的发育以某些基因的表达为标志？糖皮质激素的作用是什么 受体（GR）在胚胎和成人5-HT神经元中的作用？Deneris希望确定一个多样化的网络， 控制5-HT神经元发育和功能的不同方面的因子。将这项研究纳入 听着CacotnetreistCicesntoefrcapnrod jiedcatewisllergorteoantelyrgfaicimlitartkeesrstudniedsfuanimcteiodnaltsdtuedteierms ionfinGgRththerosuppagahtioctagermepfuollyalpleaxnpensaiondn 与P. Levitt（项目2），R. Blakely（Project 3），E. Sanders-Bush（Project 4），D. 麦克马洪（项目6）和三个孔蒂中心核心。Deneris的转基因品系将提供新的工具， 促进项目2-4和6中建议的研究。项目1的转录组数据库将提供关键的 研究小鼠5 HT神经元转录组功能和调节的参考信息， 项目2-6。项目1的研究将使未来的筛选疾病相关的遗传变异， 5 HT神经元发育控制基因。

Altered 5HT signaling has been implicated in the pathogenesis of numerous neurological and psychiatric disorders. Many of these disorders are neurodevelopmental in origin and risk for acquiring them is likely to be influenced by multiple heritable susceptibility factors. In Project 1: Genetic Networks Establishing Serotonergic Neuronal Identity, Evan Deneris hypothesizes that some of these susceptibility factors may be allelic variants of genes that govern 5HT neuron development and that these alleles may contribute to behavioral pathogenesis by adversely increasing or decreasing 5HT system activity. Although some SERT variants are identifiable risk factors for mental health disorders, the majority of genes involved in 5HT neuron development have not yet been investigated for the presence of disease-associated alleles. Advances in this area have not been made because 5HT neurons are difficult to access for molecular genetic studies. Consequently, only a small number of genes that compose the 5HT neuron developmental program have been identified. An additional critical factor that has hindered progress is that diverse methodology and expertise is required to investigate the function of 5HT neuron developmental control genes. Deneris has developed transgenic-based tools that enable direct and highly specific access to embryonic and adult 5HT neurons. The research proposed here will take advantage of these tools to interrogate the 5HT neuron transcriptome and thereby identify genes that may control 5HT neuron development and function. His proposed aims will address the following questions: What network of genes is expressed during critical stages of embryonic and postnatal 5HT neuron development? What are the differences between the rostral and caudal 5HT neuron expressed gene networks? Are different stages of 5HT neuron development marked by expression of certain sets of genes? What role does the glucocorticoid receptor (GR) play in embryonic and adult 5HT neurons? Deneris expects to identify a diverse network of fTa3ctors that govern different facets of 5HT neuron development and function. Integration of this research into ¿hearCacotnetreistCicesntoefrcapnrodjiedcatewisllergorteoantelyrgfaicimlitartkeesrstuadniedsfuanimcteiodnaltsdtuedteierms ionfinGgRththerosupgahtioctaermepfuollryalpleaxnpnredssaiondn orchestrated collaborations with P. Levitt (Project 2), R. Blakely (Project 3), E. Sanders-Bush (Project 4), D. McMahon (Project 6) and the three Conte Center Cores. Deneris' transgenic lines will provide new tools to facilitate studies proposed in Projects 2-4 and 6. Project 1's transcriptome databases will provide critical reference information for studies of mouse 5HT neuron transcriptome function and regulation proposed in Projects 2-6. Project 1 studies will enable future screens for disease relevant genetic variants in validated 5HT neuron developmental control genes.