Project 1 Genetic Networks Establishing Serontonergic Neuronal Idenity

项目 1 建立血清素能神经元身份的遗传网络

• 批准号: 7921653
• 负责人: EVAN S DENERIS
• 金额: $ 23.71万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7921653
• 关键词: Address; Adult; Alleles; Anxiety; Area; Behavior; Behavioral; Bioinformatics; Characteristics; Circadian Rhythms; Collaborations; Databases; Development; Disease; Embryo; Emotional; Flow Cytometry; Foundations; Future; Gene Expression; Gene Expression Profile; Genes; Genetic; Genetic Variation; Glucocorticoid Receptor; Goals; Ice; Immunohistochemistry; In Situ Hybridization; Knock-out; Knockout Mice; Label; Mental disorders; Methodology; Molecular Genetics; Molecular Profiling; Moods; Mus; Neurodevelopmental Disorder; Neurologic; Neurons; Pain; Pathogenesis; Pattern; Perception; Play; Predisposition; Preparation; Proteins; Proteomics; Regulation; Research; Research Personnel; Resources; Respiration; Risk; Risk Factors; Role; Serotonin; Signal Transduction; Sleep; Staging; Stress; System; Tamoxifen; Testing; Time; Transgenic Organisms; Variant; axon growth; axonal guidance; base; biological adaptation to stress; clinically relevant; energy balance; follow-up; gene function; genetic variant; nerve supply; nervous system disorder; neurochemistry; neuron development; novel marker; postnatal; programs; receptor function; recombinase; spatiotemporal; synaptogenesis; tool

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.

5HT 信号传导的改变与许多神经系统和疾病的发病机制有关。 精神疾病。这些疾病中有许多是神经发育性疾病的起源以及获得这些疾病的风险 可能受到多种遗传易感因素的影响。项目 1：遗传网络 埃文·丹尼里斯 (Evan Deneris) 建立了血清素能神经元身份，假设其中一些易感性 这些因素可能是控制 5HT 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 5HT 系统活性来促进行为发病机制。虽然 一些 SERT 变异是可识别的精神健康障碍的危险因素，大多数基因涉及 尚未研究 5HT 神经元发育是否存在与疾病相关的等位基因。 该领域尚未取得进展，因为 5HT 神经元很难进行分子分析 遗传学研究。因此，只有少数基因组成 5HT 神经元发育 方案已经确定。阻碍进步的另一个关键因素是多元化 研究 5HT 神经元发育控制的功能需要方法论和专业知识 基因。 Deneris 开发了基于转基因的工具，可以直接且高度特异性地获取 胚胎和成人 5HT 神经元。这里提出的研究将利用这些工具 询问 5HT 神经元转录组，从而识别可能控制 5HT 神经元的基因 发育和功能。他提出的目标将解决以下问题：基因网络是什么？ 在胚胎和出生后 5HT 神经元发育的关键阶段表达？有哪些 头侧和尾侧 5HT 神经元表达基因网络之间的差异？是不同阶段的 5HT 神经元发育以某些基因组的表达为标志？糖皮质激素有什么作用 受体 (GR) 在胚胎和成人 5HT 神经元中发挥作用？ Deneris 期望建立一个多元化的网络 控制 5HT 神经元发育和功能不同方面的 fTa3ctors。将此研究整合到 ¿hearCacotnetreistCicesntoefrcapnrodjiedcatewisllergorteoantelyrgfaicimlitartkeesrstuadniedsfuanimcteiodnaltsdtuedteierms ionfinGgRththerosupgahtioctaermepfuollryalpleaxnpnredssaiondn 与 P. Levitt（项目 2）、R. Blakely（项目 3）、E. Sanders-Bush（项目 4）、D. 麦克马洪（项目 6）和三个孔特中心核心。 Deneris 的转基因品系将为 促进项目 2-4 和 6 中提出的研究。项目 1 的转录组数据库将提供关键的 小鼠5HT神经元转录组功能和调控研究的参考信息 项目 2-6。项目 1 研究将使未来能够筛选经过验证的疾病相关遗传变异 5HT神经元发育控制基因。