Exploring the Role of the Prokineticin System in Human Reproduction

描述（由申请人提供）：下丘脑内独特的神经网络启动并维持人类的生殖功能。它通过协调神经网络中单一神经内分泌十肽，促性腺激素释放激素（GnRH）的合成和脉动分泌来完成这一任务。在过去的二十年中，通过研究GnRH缺乏症患者，已经发现了几个控制GnRH个体发生的基因和途径。几种G蛋白偶联受体（gpcr）及其同源配体参与了人类生殖的神经内分泌控制。然而，关于这些新基因和途径的知识仍处于早期阶段，需要进一步研究。我的研究项目的总体目标是探索prokineticin系统在控制人类生殖发育和功能的神经网络中的作用。促动素信号系统PROK2 （PROK2）和PROK2受体（PROKR2）最近被发现是小鼠和人类生殖神经内分泌控制的关键调节因子。PROK2和PROKR2在中枢神经系统中高度表达，在嗅球神经发生和随后的GnRH神经元迁移中发挥重要作用。促动素2也作为视交叉上核的关键昼夜输出分子，调节动物的摄食行为。尽管人类和小鼠的研究已经证实并确定了促动素途径在哺乳动物生殖中的关键作用，但该生物学的几个特征仍然令人困惑，这表明该途径在人类中具有更复杂的系统生物学。本研究的目的是阐明GnRH缺乏的遗传结构，并研究PROKR2突变影响受体功能的分子机制。我的第一个目的是确定PROKR2杂合突变在孤立性促性腺功能减退症（IHH）中的作用，验证GnRH缺乏患者PROKR2杂合突变不足以导致孤立性促性腺功能减退症表型的假设，但可能与第二次遗传“命中”相关。我的第二个目标是阐明保守氨基酸突变干扰PROKR2功能的机制，以识别这些氨基酸和该受体的结构域的功能，并识别与细胞内运输（伴侣蛋白）和

DESCRIPTION (provided by applicant): A unique neural network within the hypothalamus initiates and maintains reproductive function in humans. It accomplishes this task by coordinating the synthesis and pulsatile secretion of a single neuroendocrine decapeptide, gonadotropin-releasing hormone (GnRH), from this neural network. In the last two decades, several genes and pathways that govern GnRH ontogeny have been discovered by studying humans with GnRH deficiency. Several G protein-coupled receptors (GPCRs) and their cognate ligands have been implicated in the neuroendocrine control of human reproduction. However, the knowledge about many of these new genes and pathways are still in the early stages and require further investigation. The overall goal of my research project is to explore the role of th prokineticin system in the neural network that controls human reproductive development and function. The prokineticin signaling system, prokineticin 2 (PROK2) and PROK2 receptor (PROKR2), has recently emerged as a critical regulator of the neuroendocrine control of reproduction in both mice and humans. PROK2 and PROKR2 are highly expressed in the central nervous system and play an important role in olfactory bulb neurogenesis and subsequently in GnRH neuronal migration. Prokineticin 2 also acts as a key circadian output molecule from the suprachiasmatic nucleus and regulates ingestive behavior in animals. Although both human and mouse studies have confirmed and firmly established a key role of the prokineticin pathway in mammalian reproduction, several features of this biology remain puzzling, suggesting a more complex systems biology of this pathway in humans. The objective of this proposal is to clarify the genetic architecture of GnRH deficiency and to investigate the molecular mechanisms through which PROKR2 mutations affect receptor function. My first aim is to define the role of the PROKR2 heterozygous mutations in isolated hypogonadotropic hypogonadism (IHH), testing the hypothesis that heterozygous mutations in PROKR2 in patients with GnRH deficiency are not sufficient to cause the hypogonadotropic hypogonadism phenotype in isolation, but can contribute to the phenotype in association with a second genetic "hit". My second aim is to elucidate mechanisms by which mutations in conserved amino acids interfere with PROKR2 function to recognize the functions of these amino acids and domains of this receptor and also to identify proteins connected to intracellular trafficking (chaperones) and degradation pathways of GPCRs. Together, these studies will advance our understanding of the etiology of GnRH deficiency and the role of prokineticin system in this process, and will provide insights into the structure-activity relationships of the PROKR2, with potential implications for GPCR biology in general. This work will expand my research training to encompass both a molecular approach to understanding the mechanisms that cause disease and a translational approach in relating my findings to the phenotypes of patients with disorders of reproductive development and function.