Genes Controlling Assembly and Function of Serotonin Systems

描述（由申请人提供）：本提案旨在创建一个NIMH Silvio O。范德比尔特大学康特神经科学研究中心研究“基因控制血清素系统的组装和功能”。我们的中心假设是，在一个严格控制的蛋白质网络的功能和遗传变异建立神经递质5羟色胺（5 HT）在早期大脑发育的调节能力。这些变化的后果会影响整个生命，影响5-羟色胺神经元活动和5-羟色胺信号传导，并最终限制应对日常生活挑战所需的行为灵活性。为了验证这一假设并阐明这一网络，我们组建了一个由范德比尔特大学（莱维特、布莱克利、桑德斯-布什、埃米森、麦克马洪）和凯斯西储大学（德内里斯）的知名研究人员组成的跨学科团队。项目1（Deneris）鉴定了胚胎和出生后的5 HT神经元转录组，并阐明了糖皮质激素受体在5 HT神经元发育、功能和对行为的贡献中的神经元特异性功能。项目2（Levitt）探索支持5 HT在丘脑皮层和中缝回路组装中的调节作用的信号通路网络。项目3（Blakely）研究了调节抗抑郁药敏感性5-羟色胺转运蛋白（SERT）的蛋白质网络，以及与新型小鼠模型中SERT蛋白质组相关的PKG/p38 MARK信号转导改变的功能影响。项目4（Sanders-Bush）通过分析重组近交系小鼠品系的数量性状，阐明了小鼠中5 HT产生和信号传导以及5 HT连锁行为的遗传基础。项目5（Emeson）利用新型转基因小鼠模型来探索与5 HT 2C受体RNA编辑相关的生物化学、功能和行为能力。项目6（McMahon）研究了与行为节律调制相关的中缝神经元和下丘脑中缝靶点中时钟基因指定的分子网络和生理反应。我们的计划得到了行政，生物分析，生物行为和生物信息学/生物统计学核心的支持，以及范德比尔特医学院的重大投资，包括员工，设施和与项目目标相关的试点赠款计划。通过这个项目，我们试图阐明在小鼠中组织5 HT信号传导能力的基因和蛋白质网络，并将此信息与人类中的orthoprotein基因网络联系起来，以最终用于更广泛的神经科学界针对5 HT相关疾病的翻译项目。利用基于网络的工具，科学研讨会，试点资助计划和社区论坛，范德比尔特孔特神经科学研究中心将寻求向公众传播其研究结果，并激发年轻人的思想，以维持在这一重要领域的基本神经生物学基础精神疾病，包括焦虑，抑郁症，强迫症和自闭症以及常见和未来的药物治疗的探索。

Description (Provided by Applicant): This proposal seeks the creation of an NIMH Silvio O. Conte Center for Neuroscience Research at Vanderbilt University to investigate "Genes Controlling Assembly and Function of Serotonin Systems". Our central hypothesis is that functional and genetic variation in a tightly controlled network of proteins establishes modulatory capacity of the neuretransmitter serotonin (5HT) during early brain development. These variations have consequences that reverberate throughout life, impacting serotonin neuronal activity and serotonin signaling and ultimately constraining behavioral flexibility that is needed to meet the challenges of daily life. To test this hypothesis and illuminate this network, we have assembled an interdisciplinary team of established researchers at Vanderbilt University (Levitt, Blakely, Sanders-Bush, Emeson, McMahon) and Case Western Reserve (Deneris). Project 1 (Deneris) identifies embryonic and postnatal 5HT neuron transcriptomes and elucidates the serotonergic-specific function of the glucocorticoid receptor in 5HT neuron development, function and contributions to behavior. Project 2 (Levitt) explores the network of signaling pathways supporting the modulatory role of 5HT in the assembly of thalamocortical and raphe circuits. Project 3 (Blakely) investigates the protein network regulating the antidepressant-sensitive serotonin transporter (SERT) and the functional impact of altered PKG/p38 MARK signaling linked to the SERT proteome in novel mouse models. Project 4 (Sanders-Bush) elucidates the genetic underpinnings of 5HT production and signaling as well as 5HT-linked behaviors in the mouse through the analysis of quantitative traits in recombinant-inbred mouse strains. Project 5 (Emeson) utilizes novel transgenic mouse models to explore the biochemical, functional and behavioral capacities linked to editing of 5HT2C receptor RNA. Project 6 (McMahon) examines the molecular network and physiological responses specified by clock genes in both raphe neurons and raphe targets in the hypothalamus linked to the modulation of behavioral rhythms. Our program is supported by Administrative, Bioanalytical, Biobehavioral, and Bioinformatics/Biostatistics Cores as well as a significant investment of the Vanderbilt School of Medicine including staff, facilities and a pilot grant program linked to the goals of the project. Through this program, we seek to illuminate the network of genes and proteins organizing the capacity for 5HT signaling in the mouse and link this information to orthologous gene networks in humans for eventual use in translational programs that target 5HT-linked disorders by the broader neuroscience community. Using web-based tools, scientific symposia, pilot grant programs and community forums, the Vanderbilt Conte Center for Neuroscience Research will seek to disseminate its findings to the general public and excite young minds to sustain exploration in this important area of basic neurobiology underlying mental illness including anxiety, depression, obsessive-compulsive disorder, and autism as well as common and future pharmacotherapies.