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: 8134923
• 负责人: EVAN S DENERIS
• 金额: $ 23.36万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8134923
• 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.

在众多神经系统的发病机理中暗示了5HT信号的改变 精神疾病。这些疾病中有许多是神经发育的起源，并且有可能吸收它们的风险 可能会受到多种可遗传易感因素的影响。在项目1：遗传网络中 建立血清素能神经元身份，Evan Deneris假设其中一些易感性 因素可能是控制5HT神经元发展的基因的等位基因变异，这些等位基因可能 通过不利增加或减少5HT系统活性来对行为发病机理的贡献。虽然 一些SERT变体是精神健康障碍的可识别危险因素，大多数涉及的基因 尚未研究5HT神经元的发育。 由于5HT神经元的分子难以访问，因此尚未取得进展 遗传研究。因此，只有少数构成5HT神经元发育的基因 已经确定了程序。阻碍进步的另一个关键因素是潜水员 需要方法和专业知识来研究5HT神经元发育控制的功能 基因。 Deneris开发了基于转基因的工具，可直接且高度具体地访问 胚胎和成人5HT神经元。这里提出的研究将利用这些工具来 询问5HT神经元转录组，从而识别可能控制5HT神经元的基因 发展和功能。他提出的目标将解决以下问题：什么基因网络 在胚胎和产后5HT神经元发育的关键阶段表达吗？什么是 Rostral和Caudal 5HT神经元之间的差异表示基因网络？是不同的阶段 5HT神经元的发育以某些基因表达为标志？糖皮质激素是什么作用 受体（GR）在胚胎和成人5HT神经元中发挥作用？ Deneris希望确定一个多元化的网络 控制5HT神经元发展和功能不同方面的FTA3CTOR。将这项研究的整合到 �hearcAcotNetreistcicesntoefrcapnrodjiedcatewisllergorteoanteyrgfaicimlitarartkeesrstuadniedsfuanimcteioodnaltsdtuedteiermsionftheiermsionfinggrththerththerththertherthertherthertherthertherthertherthertherthertherthertherthertherthertherthertherthertherthertheremtemctaermctaermpfuollryalallyalallyallyaldnpnpnplexnpnreddnrednreddnreddnedndnreddndndndndndndndndndred and 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）和三个孔戴中心核心。 Deneris的转基因线将为 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 小鼠5HT神经元转录组功能和调节的参考信息 项目2-6。项目1研究将使未来的筛查在经过验证的疾病中相关的遗传变异 5HT神经元发育控制基因。