NEUROENDOCRINOLOGY OF PUBERTY AND SEXUAL DEVELOPMENT

青春期和性发育的神经内分泌学

• 批准号: 8357881
• 负责人: Sergio R Ojeda
• 金额: $ 5.82万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8357881
• 关键词: Astrocytes; Cell Signaling Process; Cells; Communication; Epidermal Growth Factor Receptor; ErbB4 gene; Excitatory Amino Acids; Female; Funding; Genes; Glutamates; Goals; Grant; Hypothalamic structure; Intercellular Adhesion Molecules; Ligands; Mediating; Metalloproteases; Mus; National Center for Research Resources; Neuroendocrinology; Neuroglia; Neurons; Neurosecretory Systems; Pathway interactions; Primates; Principal Investigator; Process; Puberty; Receptor Protein-Tyrosine Kinases; Regulator Genes; Research; Research Infrastructure; Resources; Sexual Development; Signaling Molecule; Source; System; Testing; Time; Transcriptional Regulation; United States National Institutes of Health; cost; homeodomain; intercellular communication; novel; receptor

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. This is a revised renewal application aimed at elucidating the neuroendocrine mechanisms underlying the initiation of female puberty. During the last funding period we examined the hypothesis that the activation of LHRH secretion at puberty requires a cell-cell communication process provided by structurally and functionally connected neuronal and glial subsets of the hypothalamus. We also began testing the hypothesis that neuron-glia bidirectional communication, and hence the pubertal process itself, is under the transcriptional control of "upstream" regulatory genes. We established the initial framework supporting both concepts by: a) defining erbB-1 and erbB-4 tyrosine kinase receptors as major components of the communication pathway used by glial cells to facilitate LHRH release, b) identifying ionotropic/metabotropic receptors as signaling molecules used by glutamatergic neurons to coordinate the facilitatory transsynaptic and glial input to LHRH neurons, and c) defining the homeodomain gene TTF-1 as an example of an upstream hierarchy of genes involved in the transcriptional control of puberty. In addition to accomplishing these goals we identified two new components of the cell-cell signaling process underlying erbB receptor-mediated glia-neuron bidirectional communication, and discovered a novel gene that might represent a second upstream component of the hypothalamic regulatory network controlling female sexual development. We now propose studies to define the importance of these newly discovered systems in neuroendocrine glia-neuronal communication and the impact they may exert on the initiation of female puberty. To this end, the following aims are proposed: 1) To test the hypothesis that TACE, a metalloproteinase involved in the ectodomain cleavage of erbB ligands and erbB receptors, is required for excitatory amino acids to induce glial TGFa release, and thus it is important for the neuron-glia mediated control of puberty. 2) To test the hypothesis that glial expression of SynCAM, an intercellular adhesion molecule found at reduced levels in astrocytes of erbB-4-deficient mice, is involved in the glial-neuron control of female puberty. 3) To test the hypothesis that TTF-1, a homeodomain gene required for the normal timing of female puberty, is an upstream coordinator of the glial-neuronal interactions underlying the pubertal activation of LHRH secretion. 4) To examine the hypothesis that a novel gene, termed EAP-1 (Enhanced At. Puberty-1) belongs - along with TTF-1 - to the hierarchy of controlling genes involved in the transcriptional regulation of the pubertal process.

该子项目是利用资源的众多研究子项目之一 由 NIH/NCRR 资助的中心拨款提供。子项目的主要支持 并且子项目的主要研究者可能是由其他来源提供的， 包括其他 NIH 来源。 子项目可能列出的总成本 代表子项目使用的中心基础设施的估计数量， NCRR 赠款不直接向子项目或子项目工作人员提供资金。 这是修订后的更新申请，旨在阐明神经内分泌 女性青春期启动的潜在机制。上次融资期间 在此期间，我们检验了青春期 LHRH 分泌激活的假设 需要由结构和功能提供的细胞间通信过程 连接下丘脑的神经元和神经胶质亚群。我们也开始测试 假设神经元-胶质细胞双向通讯，从而导致青春期 过程本身受到“上游”调节基因的转录控制。 我们通过以下方式建立了支持这两个概念的初始框架：a) 定义 erbB-1 和 erbB-4 酪氨酸激酶受体作为通讯的主要组成部分 神经胶质细胞用于促进 LHRH 释放的途径，b) 识别 离子型/代谢型受体作为谷氨酸能使用的信号分子 神经元协调 LHRH 神经元的易化跨突触和神经胶质输入， c) 定义同源域基因 TTF-1 作为上游的一个例子 参与青春期转录控制的基因层次结构。此外 为了实现这些目标，我们确定了细胞间信号传导的两个新组成部分 erbB 受体介导的胶质神经元双向通讯的潜在过程， 并发现了一个可能代表第二个上游成分的新基因 控制女性性发育的下丘脑调节网络。我们现在 提出研究来定义这些新发现的系统的重要性 神经内分泌胶质神经元通讯及其对神经内分泌的影响 女性青春期的开始。为此，提出以下目标： 1) 测试 TACE（一种参与胞外域切割的金属蛋白酶）的假设 erbB 配体和 erbB 受体的结合是兴奋性氨基酸诱导 胶质细胞TGFa的释放，因此对于神经元-胶质细胞介导的控制非常重要 青春期。 2) 检验细胞间质细胞 SynCAM 的神经胶质表达的假设 在 erbB-4 缺陷小鼠的星形胶质细胞中发现的粘附分子水平降低， 参与女性青春期的神经胶质神经元控制。 3）检验假设 TTF-1 是女性青春期正常时间所需的同源域基因，是一种 青春期神经胶质-神经元相互作用的上游协调者 激活 LHRH 分泌。 4）检验一个新基因的假设，称为 EAP-1（增强型青春期-1）与 TTF-1 一起属于以下层次： 控制参与青春期过程转录调节的基因。