Genes Controlling Assembly and Function of Serotonin Systems

描述（由申请人提供）：本提案寻求在范德比尔特大学建立NIMH Silvio O. Conte神经科学研究中心，以研究“控制血清素系统组装和功能的基因”。我们的中心假设是，在一个严格控制的蛋白质网络中，功能和遗传变异在早期大脑发育过程中建立了神经递质5 -羟色胺（5HT）的调节能力。这些变化会影响整个生命，影响血清素神经元活动和血清素信号，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（Levitt, Blakely, Sanders-Bush, Emeson, McMahon）和凯斯西储大学（Case Western Reserve）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5HT神经元转录组，并阐明了糖皮质激素受体在5HT神经元发育、功能和行为中的5 -羟色胺能特异性功能。项目2 （Levitt）探索了支持5HT在丘脑皮质和中脑回路组装中的调节作用的信号通路网络。项目3 （Blakely）在新型小鼠模型中研究了调节抗抑郁敏感血清素转运体（SERT）的蛋白质网络，以及与SERT蛋白质组相关的PKG/p38 MARK信号改变对功能的影响。Project 4 （Sanders-Bush）通过分析重组近交系小鼠的数量性状，阐明了5HT产生和信号传导以及5HT相关行为的遗传基础。Project 5 （Emeson）利用新型转基因小鼠模型探索与5HT2C受体RNA编辑相关的生化、功能和行为能力。项目6 （McMahon）研究了与行为节律调节相关的中缝神经元和下丘脑中缝靶点的时钟基因所指定的分子网络和生理反应。我们的项目得到了行政、生物分析、生物行为和生物信息学/生物统计学核心以及范德比尔特医学院的重大投资的支持，包括工作人员、设施和与项目目标相关的试点拨款计划。通过这个项目，我们试图阐明在小鼠中组织5HT信号能力的基因和蛋白质网络，并将这些信息与人类的同源基因网络联系起来，最终用于更广泛的神经科学界针对5HT相关疾病的翻译项目。Vanderbilt Conte神经科学研究中心将利用网络工具、科学专题讨论会、试点资助计划和社区论坛，向公众传播其研究成果，并激发年轻人继续探索这一重要的基础神经生物学领域，包括焦虑、抑郁、强迫症和自闭症等精神疾病，以及常见和未来的药物治疗。

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.