Kisspeptin/GPR54 in the Female Neuroendocrine Axis

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DESCRIPTION (provided by applicant): The KiSS-1 gene codes for a family of peptides called kisspeptins, which bind to a G protein-coupled receptor known as GPR54. KiSS-1 and GPR54 are expressed in the forebrain, and mutations in the GPR54 gene cause hypogonadotropic hypogonadism in humans and mice. Kisspeptins stimulate gonadotropin- releasing hormone (GnRH) and gonadotropin (LH and FSH) secretion, and the KiSS-1 gene is regulated by gonadal steroids-suggesting that kisspeptin signaling through GPR54 plays a role in the neuroendocrine regulation of reproduction. The overall goal of this research is to understand the physiological function of kisspeptins in the regulation of gonadotropin secretion in the female rat and mouse. Our first objective is to assess the role of kisspeptins in the preovulatory gonadotropin surge. Here, we will test whether kisspeptin/ GPR54 mRNA signaling pathway is critical for the generation an estrogen (E)/progesterone (P)-induced LH surge. We will also evaluate the possibility that KiSS-1 neurons of the anteroventral periventricular nucleus (AVPV) mediate the effects of E, P, and circadian signals from the suprachiasmatic nucleus (SCN) on the generation of LH surges. The second objective is to investigate the role of kisspeptins in the onset of puberty and sexual differentiation of the LH surge mechanism. In these experiments, we will evaluate changes in kisspeptin neurons over sexual development and determine whether these changes are dependent on sex steroids. We will also investigate whether puberty is associated with an increase in the ability of kisspeptins to stimulate the activity of GnRH neurons. In addition, we will determine whether kisspeptin/GPR54 signaling in GnRH neurons plays a critical role in puberty by evaluating the effects of introducing a functional GPR54 gene into GnRH neurons of GPR54 KOs. Finally, we will investigate whether sex differences in the expression of KiSS-1 and GPR54 are attributable to organizational processes that during the neonatal critical period or hormone-dependent activational events at puberty. Elucidating the role of kisspeptins in the development and regulation of gonadotropin secretion in females may improve our understanding of idiopathic hypogonadotropic hypogonadism in humans and could provide the scientific rationale for improved therapies to treat precocious or delayed puberty and infertility. It's also conceivable that this knowledge could serve as the basis for the development of new and better strategies for hormonal contraception.