Novel Mechanisms Underlying the Transsynaptic Control of LHRH Release

LHRH 释放的跨突触控制的新机制

基本信息

批准号：
7788347
负责人：
Sergio R Ojeda
金额：
$ 7.56万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-04-01 至 2011-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7788347
关键词：
Acids Adult Amenorrhea Amino Acid Neurotransmitters Attention Behavior Brain Cells Communication Competence Coupled DNA DNA Microarray Chip Family Female Gene Transfer Genes Glutamate Transporter Glutamates Gonadotropin Hormone Releasing Hormone Human Hypothalamic structure Infertility Integral Membrane Protein Interneurons Ion Transport Kallmann Syndrome Lead Mediating Modeling Molecular Molecular Genetics Monkeys Nature Neurons Neurosecretion Normalcy Open Reading Frames Periodicity Play Primates Proteins Rattus Reagent Regulation Regulatory Element Reproduction Research Rodent Rodent Model Role Signal Pathway Signal Transduction Synapses Syndrome System Techniques Testing Transgenic Organisms base cDNA Arrays gain of function gene discovery mRNA Differential Displays member migration nerve supply neuronal circuitry neuronal excitability neurotransmission novel postsynaptic receptor reproductive research study response

项目摘要

Luteinizing hormone-releasing hormone (LHRH) secretion is controlled by transsynaptic inputs of both excitatory and inhibitory nature, in addition to gila-to-neuron signaling pathways. While neurons that utilize gamma aminobutydc acid (GABA) for synaptic communication provide the major inhibitory input to the LHRH neuronal network, the bulk of the excitatory control of LHRH release is furnished by neuronal circuitries that use glutamate for neurotransmission. During the past period of support we focused our attention on the GABAergic system, and demonstrated that - contrary to the prevailing dogma - the direct GABAA receptor (R)-mediated input to LHRH neurons is excitatory, and not inhibitory. Using gene transfercell 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 prepared the molecular and genetic reagents to define the importance of such mechanisms in the control of adult LHRH neuronal function. In addition, we used gene discovery approaches to identify genes that appear to be upstream components of the dual inhibitory/excitatory transsynaptic control of LHRH neurosecretion. Studies are now proposed to define the impact that each of these regulatory components may exert on the functional competence of LHRH neurons during female adulthood. To this end, the following aims are proposed: 1) to test the hypothesis that excitatory GABAAR-mediated inputs exerted directly on LHRH neurons are required for normal reproductive cyclicity, 2) to determine the role that members of the novel FXYD family of ion transport-controlling proteins, play in the regulation of LHRH secretion, 3) to test the hypothesis that Nell2, a novel gene specifically expressed in glutamatergic neurons, is an upstream regulatory element required for the glutamatergic control of reproduction, and 4) to define the role that a novel gene known as C14ORF4 may play in coordinating the dual excitatory/inhibitory transsynaptic control of reproductive cyclicity. We anticipate that the concepts derived from these studies will lead to a better understanding of the cellular mechanisms underlying the loss of reproductive competence in human syndromes such as hypothalamic amenorrhea and idiopathic hypothalamic hypogonadism.

黄体生成素释放激素 (LHRH) 的分泌受两者的突触输入控制除了吉拉到神经元信号通路之外，还具有兴奋性和抑制性。虽然利用的神经元用于突触通讯的γ氨基丁酸（GABA）为突触通讯提供主要的抑制输入 LHRH 神经元网络，LHRH 释放的大部分兴奋性控制由神经元提供使用谷氨酸进行神经传递的电路。在过去的支持期间，我们重点关注对 GABAergic 系统的关注，并证明 - 与普遍的教条相反 - 直接 GABAA 受体 (R) 介导的 LHRH 神经元输入是兴奋性的，而不是抑制性的。使用基因转移细胞我们证明了嫁接技术和转基因方法需要 GABA 能基调 LHRH 神经元迁移和成年女性生殖能力均正常。我们还确定了研究人员研究了 GABAAR 介导的 LHRH 神经元兴奋的细胞机制，并制备了分子和遗传试剂来定义此类机制在控制成人 LHRH 神经元功能中的重要性。此外，我们使用基因发现方法来识别似乎是 LHRH 神经分泌双重抑制/兴奋性突触控制上游成分的基因。现在提出研究来定义这些调节成分中的每一个可能对女性成年期间 LHRH 神经元的功能能力产生的影响。为此，提出以下目标：1) 检验正常生殖周期需要直接作用于 LHRH 神经元的兴奋性 GABAAR 介导输入的假设，2) 确定新型 FXYD 离子转运家族成员的作用-控制蛋白，在 LHRH 分泌的调节中发挥作用，3) 检验 Nell2（一种在谷氨酸能神经元中特异性表达的新基因）的假设，它是 LHRH 分泌所需的上游调节元件生殖的谷氨酸控制，4) 定义称为 C14ORF4 的新基因在协调生殖周期的双重兴奋/抑制性跨突触控制中可能发挥的作用。我们预计，从这些研究中得出的概念将有助于更好地理解人类综合征（例如下丘脑闭经和特发性下丘脑性腺功能减退症）生殖能力丧失的细胞机制。