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促进生殖科学劳动力多样性的合作研究伙伴关系（U 01）的回应，标题为生殖中的Kisspeptin调节和GPR 54信号传导。该应用程序是约翰霍普金斯大学医学院的Sally Radovick博士和Andrew Wolfe博士以及摩根州立大学的格洛丽亚霍夫曼博士之间的研究伙伴关系。摩根州立大学和约翰霍普金斯大学的本科生将在这一合作奖励机制下招募和指导。课程将包括教学讲座，广泛的实验室为基础的研究和职业咨询。 由调查员组成的指导委员会将指导这一进程。LH的释放受神经激素促黄体生成素释放激素（LHRH）的调节。最近，通过G蛋白偶联受体GPR 54发出信号的肽kisspeptin（KP）被发现是LHRH调节的关键组分。KP在LHRH神经元水平的直接作用的证据来自于LHRH表达细胞系的解剖学和体外研究。KP神经元的两个主要群体被描述在下丘脑：一个在弓状核（Arc）和一个在AVPV。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。弧人口是不是性二态性，并牵连在基础LHRH的释放和负反馈在两性，但它是如何做到这一点是未知的。虽然KP调节的某些方面在灵长类动物中被保留，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间被保留的分辨率很小。该提案将检查KP神经元与啮齿动物与灵长类动物中LHRH系统的连接性，并且还将产生一种floxed GPR 54小鼠系，以特异性地消融LHRH神经元中的GPR 54，以研究青春期发作和雌激素反馈调节以及LHRH神经元中的细胞变化。综上所述，本研究将阐明KP-GPR 54信号通路在雌激素反馈调节中的作用及其在生殖中枢的位置。 公共卫生相关性：目标是为选定的本科生提供来自两个机构的独特资源，这些资源专注于生殖生物学领域的广泛教学和实验室经验。与学术研究人员合作学习，学生将研究控制哺乳动物繁殖的调节机制。

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.