2/2 Kisspeptin Regulation and GPR54 Signaling in Reproduction

描述（由申请人提供）：本提案是对RFA-HD-09-008合作研究伙伴关系促进生殖科学劳动力多样性（U01）的回应，题为“Kisspeptin调节和GPR54信号传导在生殖中”。该应用程序是博士之间的研究合作伙伴关系。约翰霍普金斯大学医学院的Sally Radovick和Andrew Wolfe以及摩根州立大学的Gloria Hoffman博士。根据这一合作奖励机制，将招收摩根州立大学和约翰霍普金斯大学的本科生并对其进行指导。课程将包括教学讲座、广泛的实验室研究和职业咨询。由调查人员组成的指导委员会将指导这一进程。黄体生成素的释放受神经激素、促黄体生成素释放激素（LHRH）的调控。最近，通过g蛋白偶联受体GPR54发出信号的肽kisspeptin （KP）被发现是调控LHRH的关键成分。KP在LHRH神经元水平上的直接作用的证据来自于对表达LHRH的细胞系的解剖和体外研究。在下丘脑中描述了两个主要的KP神经元群：一个在弓状核（Arc）中，一个在AVPV中。AVPV KP神经元直接投射到LHRH神经元，并在LH激增时刺激LHRH神经元。Arc人群不是两性二态的，并且与两性的基础LHRH释放和负反馈有关，但它是如何实现的尚不清楚。虽然KP调控的某些方面在灵长类动物中得到了保留，但关于AVPV群体是否存在，以及KP神经元与LHRH和其他系统的连接是否在物种中得到保留，我们几乎没有定论。本研究将在啮齿类动物和灵长类动物中研究KP神经元与LHRH系统的连接，并将生成一个固定的GPR54小鼠系，以特异性地切除LHRH神经元中的GPR54，以研究青春期发作和雌激素反馈调节以及LHRH神经元的细胞变化。综上所述，本研究将揭示KP-GPR54信号通路在雌激素反馈调控中的作用及其在生殖中轴的位置。

DESCRIPTION (provided by applicant): This proposal is in response to RFA-HD-09-008 Cooperative Research Partnerships to Promote Workforce Diversity in the Reproductive Sciences (U01), entitled, Kisspeptin Regulation and GPR54 Signaling in Reproduction. The application is a research partnership among Drs. Sally Radovick and Andrew Wolfe at Johns Hopkins University School of Medicine and Dr. Gloria Hoffman at Morgan State University. Undergraduate students from Morgan State University and Johns Hopkins University will be recruited and mentored under this collaborative award mechanism. The curriculum will include didactic lectures, a wide breadth of laboratory based studies and career counseling. A Steering Committee comprised of the investigators will guide the process. The release of LH is under the regulation of the neurohormone, luteinizing hormone releasing hormone (LHRH). Recently, the peptide kisspeptin (KP) that signals through a G-protein coupled receptor, GPR54, was found to be a key component in the regulation of LHRH. Evidence for a direct role for KP at the level of the LHRH neuron comes from anatomical and in vitro studies in LHRH expressing ceil lines. Two principal populations of KP neurons are described in the hypothalamus: one in the arcuate nucleus (Arc) and one in the AVPV. The AVPV KP neurons project directly to LHRH neurons and stimulate LHRH neurons at the time of an LH surge. The Arc population is not sexually dimorphic and is implicated in basal LHRH release and negative feedback in both sexes, but how it does so is unknown. While some aspects of KP regulation are preserved in primates, there is little resolution as to whether the AVPV population is present, and whether connections of the KP neurons to LHRH and other systems are preserved across species. This proposal will examine the connectivity of KP neurons with the LHRH system in rodents vs. primates and will also generate a floxed GPR54 mouse line to specifically ablate GPR54 in the LHRH neuron to study pubertal onset and estrogen feedback regulation in addition to cellular changes in LHRH neurons. In summary, this proposal will delineate both the role of KP-GPR54 signaling in estrogen feedback regulation and its locus in the central reproductive axis. PUBLIC HEALTH RELEVANCE: The goal is to provide selected undergraduates the unique resources available from two institutions focused on a broad spectrum of didactic and laboratory experiences in the field of reproductive biology. Partnering to learn with academic researchers, the students will study regulatory mechanisms controlling mammalian reproduction.