KiSS-1/GPR54 and the Reproductive Neuroendocrine Axis

描述(由申请人提供)：人类和小鼠在G偶联受体GPR54上有功能突变，促性腺激素水平较低，因此无法经历正常的青春期成熟。KISS-1基因产物被称为KISS-Peptins，被认为是GPR54的内源性配体。KiSS-1和GPR54在前脑控制生殖的区域表达，中央给药KISS-1和GPR54刺激啮齿动物和灵长类动物促性腺激素的分泌。这些观察结果表明，GPR54的激活对于青春期发育的正常进行和成人生殖功能的维持是必不可少的。本项目的目的是阐明KiSS-1基因产物(特别是Mestatin)和GPr54在神经内分泌生殖轴中的作用，重点研究它们在性激素对促性腺激素分泌的负反馈和正反馈控制中的可能作用，以及在决定青春期开始方面的作用。阐明Mestatin和GPr54在生殖控制中的功能意义将有助于进一步深入了解人类特发性低促性腺激素低促性腺功能低下症的发病机制，并为新的治疗方法提供科学依据。

DESCRIPTION (provided by applicant): Humans and mice having dysfunctional mutations in the G-coupled receptor GPR54 have low gonadotropin levels and thus fail to undergo normal pubertal maturation. KiSS-1 gene products, known as kisspeptins, are thought to be the endogenous ligands for GPR54. KiSS-1 and GPR54 are expressed in areas of the forebrain that control reproduction and centrally-administered kisspeptins stimulate gonadotropin secretion in the rodent and primate. These observations suggest that activation of GPR54 is essential for the normal progression of pubertal development and the maintenance of reproductive function in the adult. The goal of this project is to elucidate the role of the KiSS-1 gene products (particularly Mestatin) and GPR54 in the neuroendocrine reproductive axis, focusing on their possible role in the negative and positive feedback control of gonadotropin secretion by sex steroids and in determining the onset of puberty. Elucidating the functional significance of Mestatin and GPR54 in the control of reproduction should provide further insight into the mechanisms responsible for idiopathic hypogonadotropic hypogonadism in humans and could provide scientific rationale for new therapies to treat precocious or delayed puberty and infertility.