Mechanisms Underlying GnRH Metabolite Action

GnRH 代谢作用的机制

• 批准号: 1052288
• 负责人: Tao-Yiao Wu
• 金额: $ 48万
• 依托单位: Henry M Jackson Fdn for Advmt of Military Medicine
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1052288&HistoricalAwards=false
• 关键词: Mechanisms; Underlying; GnRH; Metabolite; Action

Gonadotropin-releasing hormone (GnRH) was first isolated in mammals and shown to be the primary regulator of the reproductive system. After this initial discovery, GnRH has been shown to be part of a larger family of similar peptides found in the brain and other tissues. To date, over 20 family members have been identified in vertebrate and invertebrates, and they have been shown to have diverse functions. As with most peptides, GnRH is regulated at the synthesis level (gene expression and translation) and at secretion. In addition, 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 a subproduct, GnRH-(1-5). This subproduct of GnRH, GnRH-(1-5) is bioactive and has been shown to regulate gene expression and facilitate reproductive behavior in brain and other tissues. Dr. Wu?s laboratory recently identified an orphan G-protein coupled receptor (GPR) that binds to GnRH-(1-5) with high affinity and this receptor is likely to be the mediator of GnRH-(1-5) activities. To that end, this project will use two physiological approaches and an anatomical approach to test this hypothesis. These studies will identify a ligand and a function for an orphan receptor. The collective data will underscore the importance of peptide processing in regulating neurobiological processes that is beyond the attributes of the parent peptide ? an evolutionary influence to increase diversity. The results of this study and the identification of a novel receptor may also resolve many present quandaries in the current utilization of the parent peptide. Broader Impact: The project will include a significant training component in which apostdoctoral fellow, 1-2 graduate students and at least 6 college students and highschool students will receive training in neuroendocrine techniques. Each student will be involved in one specific aim supervised by a senior member of the laboratory. The high school student will participate in lab meetings, they will conduct some of the experiments and present at high school?s science fair, ultimately submitting their work to local and national science fairs and competitions.

促性腺激素释放激素（GnRH）首先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。 在这一初步发现之后，GnRH 已被证明是在大脑和其他组织中发现的一个更大的类似肽家族的一部分。 迄今为止，已在脊椎动物和无脊椎动物中鉴定出20多个家族成员，并且它们已被证明具有不同的功能。 与大多数肽一样，GnRH 在合成水平（基因表达和翻译）和分泌水平受到调节。 此外，GnRH 由锌金属内肽酶 EC 3.4.24.15 (EP24.15) 加工，在十肽 (Tyr5-Gly6) 的第 5 个和第 6 个残基之间的共价键处裂解激素，形成副产物 GnRH-(1 -5）。 GnRH 的这种子产物 GnRH-(1-5) 具有生物活性，已被证明可以调节基因表达并促进大脑和其他组织的生殖行为。 吴博士的实验室最近发现了一种孤儿G蛋白偶联受体(GPR)，它以高亲和力与GnRH-(1-5)结合，并且该受体很可能是GnRH-(1-5)活性的介体。 为此，该项目将使用两种生理学方法和一种解剖学方法来检验这一假设。 这些研究将鉴定孤儿受体的配体和功能。 集体数据将强调肽加工在调节神经生物学过程中的重要性，这超出了母肽的属性？增加多样性的进化影响。 这项研究的结果和新受体的鉴定也可能解决目前母肽应用中存在的许多难题。 更广泛的影响：该项目将包括一个重要的培训部分，其中博士后研究员、1-2 名研究生和至少 6 名大学生和高中生将接受神经内分泌技术的培训。每个学生将在实验室高级成员的监督下参与一个特定目标。高中生将参加实验室会议，他们将进行一些实验并在高中的科学博览会上展示，最终将他们的作品提交给当地和国家的科学博览会和竞赛。