The GnRH Metabolite, GnRH-(1-5), Functions via an orphan receptor, GPR173

GnRH 代谢物 GnRH-(1-5) 通过孤儿受体 GPR173 发挥作用

• 批准号: 8623243
• 负责人: T JOHN WU
• 金额: $ 7.8万
• 依托单位: HENRY M. JACKSON FDN FOR THE ADV MIL/MED
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-10 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8623243
• 关键词: Affinity; Agonist; Amino Acids; Anorexia; Antisense Oligonucleotides; Anxiety Disorders; Behavior; Binding; Biological Assay; Brain; Cell Nucleus; Child; Cleaved cell; Clinical; Complex; Data; Development; Disease; Down-Regulation; Drug Targeting; FDA approved; Female; Fertility; Funding; Future; Gene Expression; Goals; Gonadotropin Hormone Releasing Hormone; Gonadotropin-Releasing Hormone Receptor; Hemorrhage; Homeostasis; Hormones; Hypothalamic structure; Infertility; Laboratories; Ligands; Location; Lordosis; Mammals; Mediating; Mental Depression; Mental Health; Metabolic; Metabolic Diseases; Metalloendopeptidases; Modeling; Neurobiology; Neurons; Neurosecretory Systems; Obesity; Orphan; Ovarian; Parents; Peptides; Phenotype; Pituitary Gonadotropins; Plasma; Play; Precocious Puberty; Principal Investigator; Process; Production; Psyche structure; Puberty; Rattus; Regulation; Relative (related person); Reproduction; Reproductive Behavior; Reproductive system; Research; Risk; Role; Sampling; Sprague-Dawley Rats; Structure; Syndrome; Tail; Techniques; Testing; Time; Vagina; Variant; Zinc; age related; base; boys; clinical application; covalent bond; girls; human GNRH1 protein; human GPRC5C protein; inhibitor/antagonist; mRNA Expression; male; migration; model development; neutralizing antibody; physical conditioning; prepuberty; prevent; programs; protein expression; public health relevance; receptor; reproductive function; sex; social; young adult

Program Director/Principal Investigator (Last, First, Middle): Wu, T. John Project Summary Disorders of puberty in both boys and girls are increasingly recognized for its impact on mental, social and physical health. There are significant negative correlations between precocious puberty with metabolic disorders such as obesity, anorexia and polycystic ovarian syndrome. Likewise, there is also a correlation with mental health consequence including depression and anxiety disorders. Gonadotropin-releasing hormone (GnRH) was first isolated in the mammal and shown to be the primary regulator of the reproductive system through its initiation of pituitary gonadotropin release. During development, an increase in GnRH release occurs that is critical for the initiation of puberty. This increase is attributable, at least in part, to activation of the GnRH neurosecretory system. Discerning the underlying cause of central disorder of puberty remains an important research effort. In addition to the complex regulation of GnRH synthesis, release, and function, further evidence suggests that the processing of GnRH produces yet another layer of complexity in its activity. GnRH is processed by a zinc metalloendopeptidase EC 3.4.24.15 (EP24.15) that cleaves the hormone at the covalent bond between the 5th and 6th residue of the decapeptide (Tyr5-Gly6) to form GnRH-(1-5). We have shown that GnRH-(1-5) is not merely a degradation product but regulates a number of functions related to reproduction. These include facilitation of lordosis behavior, autoregulation of its gene expression and secretion as well as regulate GnRH neuronal migration. Interestingly, there is little evidence to suggest that GnRH-(1-5) may bind to its cognate receptor, the GnRH receptor. Our laboratory recently identified the orphan G-protein coupled receptor (GPR)-173 to bind to GnRH-(1-5) with high affinity. Not much is known about GPR173. Our preliminary results show that GPR173 expression is increased during puberty. Thus, we wish to determine if GnRH-(1-5) may be involved in regulating puberty via GPR173. To that end, we propose 2 specific aims to test the hypothesis that the increase in GnRH neuronal activity during puberty is mediated by GnRH-(1-5) via GPR173. We will approach these studies by describing the anatomical localization of GPR173 (Aim 1) and by determining whether the timing of puberty is altered when GPR173 expression is down- regulated. These studies will use the well characterized Sprague Dawley rat model of puberty. Specific Aim 1 will determine the neuroanatomical expression of GPR173 in male and female rats before and after the onset of puberty. These studies will include immunocytochemical studies examining its expression in a rostro-caudal manner as well as its potential co-localization with the GnRH neuron. We will determine the GPR173 protein and mRNA expression levels. Specific Aim 2 will determine the role of GPR173 in mediating puberty. Antisense oligonucleotides to GPR173 will be administered to pre-pubertal female rats to determine whether its down-regulation may alter the timing of puberty. Inhibitors to EP24.15 will also be administered to prevent GnRH-(1-5) production. PHS 398/2590 (Rev. 06/09) Page 2 Continuation Format Page

项目总监/首席研究员（姓、名、中）：Wu, T. John 项目概要 人们越来越认识到男孩和女孩的青春期障碍对心理、社会和心理的影响。 身体健康。性早熟与代谢呈显着负相关 肥胖、厌食症和多囊卵巢综合症等疾病。同样，也存在相关性 心理健康后果包括抑郁症和焦虑症。促性腺激素释放激素 (GnRH) 首次在哺乳动物中分离出来，并被证明是生殖系统的主要调节剂 通过启动垂体促性腺激素的释放。在发育过程中，GnRH 释放增加 发生这对于青春期的开始至关重要。这种增长至少部分归因于激活 the GnRH neurosecretory system.辨别青春期中枢失调的根本原因仍然是一个难题 重要的研究工作。除了 GnRH 合成、释放和功能的复杂调节之外， 进一步的证据表明，GnRH 的加工在其活性中产生了另一层复杂性。 GnRH 由锌金属内肽酶 EC 3.4.24.15 (EP24.15) 处理，该酶在 十肽 (Tyr5-Gly6) 的第 5 个和第 6 个残基之间形成共价键，形成 GnRH-(1-5)。我们有 表明 GnRH-(1-5) 不仅仅是一种降解产物，还调节与 生殖。这些包括促进脊柱前凸行为、其基因表达的自动调节以及 分泌以及调节 GnRH 神经元迁移。有趣的是，几乎没有证据表明 GnRH-(1-5) 可以与其同源受体（GnRH 受体）结合。我们的实验室最近确定了孤儿 G 蛋白偶联受体 (GPR)-173 以高亲和力与 GnRH-(1-5) 结合。对此了解不多 探地雷达173。我们的初步结果表明，GPR173 表达在青春期期间增加。因此，我们希望 确定 GnRH-(1-5) 是否可能通过 GPR173 参与调节青春期。为此，我们建议2 具体目的是检验青春期 GnRH 神经元活性增加是由以下因素介导的假设： GnRH-(1-5) 通过 GPR173。我们将通过描述 GPR173 的解剖定位来进行这些研究 （目标 1）并确定当 GPR173 表达下降时青春期的时间是否会改变 受监管。这些研究将使用特征明确的 Sprague Dawley 大鼠青春期模型。具体目标 1 将测定雄性和雌性大鼠发病前后GPR173的神经解剖学表达 青春期的。这些研究将包括免疫细胞化学研究，检查其在头尾神经中的表达 方式及其与 GnRH 神经元的潜在共定位。我们将确定 GPR173 蛋白 和 mRNA 表达水平。具体目标 2 将确定 GPR173 在调节青春期中的作用。 GPR173 的反义寡核苷酸将被给予青春期前的雌性大鼠以确定其是否 下调可能会改变青春期的时间。 EP24.15 抑制剂也将被施用以防止 GnRH-(1-5) 的产生。 PHS 398/2590 (Rev. 06/09) 第 2 页 继续格式页