1/2 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(U01)的回应，题为《生殖中的Kispeptin监管和GPR54信号传递》。该申请是约翰·霍普金斯大学医学院的萨利·拉多维克博士和安德鲁·沃尔夫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被招募和指导。课程将包括授课、广泛的基于实验室的研究和职业咨询。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--黄体生成素释放激素(LHRH)的调节。最近发现，通过G蛋白偶联受体GPr54传递信号的多肽Kisspeptin(KP)是调节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对LHRH表达细胞系的解剖学和体外研究。下丘脑有两种主要的KP神经元：一种在弓状核(Arc)，另一种在AVPV。Avpv KP神经元直接投射到LHRH神经元，并在LH峰时刺激LHRH神经元。Arc群体不是性别二态的，与基础LHRH释放和负反馈有关，但它是如何做到这一点的尚不清楚。虽然Kp调节的某些方面在灵长类动物中保留了下来，但对于AvPV种群是否存在，以及Kp神经元与LHRH和其他系统的连接是否在物种之间保存下来，几乎没有解决的问题。这项建议将在啮齿类动物和灵长类动物中检测KP神经元与LHRH系统的连通性，并将产生一个Gpr54小鼠系来特异性地去除LHRH神经元中的Gpr54，以研究青春期开始和雌激素反馈调节，以及LHRH神经元的细胞变化。综上所述，本研究将阐明Kp-Gpr54信号在雌激素反馈调节中的作用及其在中央生殖轴中的位置。

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.