NOVEL MECHANISMS UNDERLYING THE TRANSSYNAPTIC CONTROL OF LHRH RELEASE

LHRH 释放的跨突触控制的新机制

• 批准号: 7958399
• 负责人: Sergio R Ojeda
• 金额: $ 3.62万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-04 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7958399
• 关键词: Adult; Amenorrhea; Cells; Communication; Competence; Computer Retrieval of Information on Scientific Projects Database; Family; Female; Funding; Gene Transfer; Genes; Glutamates; Gonadotropin Hormone Releasing Hormone; Grant; Human; Hypothalamic structure; Institution; Ion Transport; Kallmann Syndrome; Mediating; Nature; Neuroglia; Neurons; Normalcy; Periodicity; Play; Primates; Proteins; Regulation; Regulatory Element; Reproduction; Research; Research Personnel; Resources; Role; Signal Pathway; Source; Synapses; Syndrome; Techniques; Testing; Transgenic Organisms; United States National Institutes of Health; gamma-Aminobutyric Acid; member; migration; novel; receptor; reproductive

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Luteinizing hormone-releasing hormone (LHRH) secretion is controlled by transsynaptic inputs of both excitatory and inhibitory nature, in addition to glia-to-neuron signaling pathways. Neurons that utilize gamma aminobutyric acid (GABA) for synaptic communication provide the major inhibitory input to the LHRH neuronal network. We have demonstrated that, contrary to the prevailing dogma, the direct GABAA receptor (R)-mediated input to LHRH neurons is excitatory and not inhibitory. Using gene transfer-cell grafting techniques and transgenic approaches we demonstrated that a GABAergic tone is required for the normalcy of both LHRH neuronal migration and adult female reproductive capacity. We also identified the cellular mechanisms underlying the GABAAR-mediated excitation of LHRH neurons and identified genes that appear to be upstream components of the dual inhibitory/excitatory transsynaptic control of LHRH secretion. Studies are now being conducted to define the impact that each of these regulatory components may exert on the functional competence of LHRH neurons during female adulthood. The hypotheses being tested include: 1) that excitatory GABAAR-mediated inputs exerted directly on LHRH neurons are required for normal reproductive cyclicity, 2) that members of the novel FXYD family of ion transport-controlling proteins play in the regulation of LHRH secretion, 3) that Nell2, a novel gene specifically expressed in glutamatergic neurons, is an upstream regulatory element required for the glutamatergic control of reproduction, and 4) that a novel gene known as C14ORF4 plays a role in coordinating the dual excitatory/inhibitory transsynaptic control of reproductive cyclicity. The concepts derived from these studies are expected to increase our understanding of the cellular mechanisms underlying the loss of reproductive competence in human syndromes such as hypothalamic amenorrhea and idiopathic hypothalamic hypogonadism.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目及 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 除了神经胶质细胞到神经元的信号通路外，黄体生成素释放激素 (LHRH) 的分泌还受到兴奋性和抑制性突触输入的控制。利用 γ 氨基丁酸 (GABA) 进行突触通讯的神经元为 LHRH 神经元网络提供主要的抑制输入。我们已经证明，与普遍的教条相反，GABAA 受体 (R) 介导的 LHRH 神经元的直接输入是兴奋性的，而不是抑制性的。使用基因转移细胞移植技术和转基因方法，我们证明 GABA 能基调是 LHRH 神经元迁移和成年女性生殖能力正常化所必需的。我们还确定了 GABAAR 介导的 LHRH 神经元兴奋的细胞机制，并确定了似乎是 LHRH 分泌的双重抑制/兴奋性跨突触控制的上游成分的基因。目前正在进行研究以确定这些调节成分中的每一个可能对女性成年期 LHRH 神经元的功能产生的影响。正在测试的假设包括：1) 正常生殖周期需要直接作用于 LHRH 神经元的兴奋性 GABAAR 介导的输入，2) 离子转运控制蛋白的新型 FXYD 家族成员在 LHRH 分泌的调节中发挥作用，3 ) Nell2 是一种在谷氨酸能神经元中特异性表达的新基因，是谷氨酸能控制生殖所需的上游调控元件，4) 一种称为 Nell2 的新基因C14ORF4 在协调生殖周期的双重兴奋/抑制性跨突触控制中发挥作用。从这些研究中得出的概念预计将增加我们对人类综合征（例如下丘脑闭经和特发性下丘脑性腺功能减退症）生殖能力丧失背后的细胞机制的理解。