Kisspeptin signaling in the brain

描述(由申请人提供)：下丘脑中的Kispeptin(KISSI)神经元在维持基础黄体生成素(LH)分泌和产生排卵所需的排卵前促性腺激素释放激素(GnRH)高峰方面发挥着重要作用。这项建议的首要目标是了解Kispeptin在生殖调节中的生理功能，并评估其与避孕和治疗发育和生殖障碍的相关性。相应地，这项建议分为两个特定的目标，将1)解决机制，如何在性别分化的前腹侧脑室周围核(AVPV)的Kispeptin神经元被性腺激素激活，以诱导排卵前GnRH/LH峰，和2)评估Kispeptin拮抗剂的治疗潜力。具体地说，目标1将验证这样一种假设，即AVPV的Kissi神经元中的孕激素受体(PR)信号在GnRH/LH峰的门控中发挥重要作用。我将研究雌激素(E_2)的存在是否上调动静脉曲张Kissi神经元PR的表达，以及长期的孕酮(P)治疗是否抑制Kissi神经元的激活，就像它对GnRH/LH峰所起的作用一样。此外，我将确定单独使用E2是否会引起Kissi的日常激活。最后，我将确定功能性PR的存在是否对E2单独重复激活Kissi神经元的能力至关重要。AIM 2采用翻译方法来解决最近发现的基斯尔拮抗剂多肽234的用途。这种药物已被证明在注射到脑室时扰乱了GnRH/LH分泌的神经内分泌调节；然而，当在血脑屏障外给药时，其阻断中枢Kispeptin活性的能力尚未得到评估。我将测试系统用肽234阻断黄体生成素峰值、扰乱性腺切除后黄体生成素升高和动情周期、防止青春期开始的效果。关联性。阐明Kispeptin在控制促性腺激素分泌中的意义可能有助于进一步了解特发性低促性腺激素低促性腺功能低下的发病机制。此外，这项对肽234的研究可能为生殖障碍(例如，性早熟、子宫内膜异位症和转移性前列腺癌)的可能临床治疗奠定基础。同样可以想象的是，这一知识可以作为开发新的和更好的激素避孕(无论是对男性还是女性)或诱导排卵的策略的基础。

DESCRIPTION (provided by applicant): Kisspeptin (Kissi) neurons in the hypothalamus play an essential role in the maintenance of basal luteinizing hormone (LH) secretion and in generating the preovulatory gonadotropin-releasing hormone (GnRH) surge required for ovulation. The overarching goal of this proposal is to understand the physiological function of kisspeptin in the regulation of reproduction, and to evaluate its relevance for contraception and the treatment of developmental and reproductive disorders. Correspondingly, this proposal is divided in to two specific aims that will 1) address the mechanisms whereby kisspeptin neurons in the sexually differentiated anteroventral periventricular nucleus (AVPV) are activated by gonadal steroids to induce the preovulatory GnRH/LH surge, and 2) evaluate the therapeutic potential of a kisspeptin antagonist. Specifically, Aim 1 will test the hypothesis that progesterone receptor (PR) signaling in Kissi neurons of the AVPV plays an important role in gating the GnRH/LH surge. I will investigate whether the presence of estradiol (E2) up-regulates PR expression in Kissi neurons in the AVPV and whether long-term progesterone (P) treatment inhibits the activation of Kissi neurons, much as it does for the GnRH/LH surge. Additionally, I will determine whether E2 alone elicits daily activation of Kissi. Finally, I will determine whether the presence of functional PR is critical for the ability of E2 alone to repeatedly activate Kissi neurons. Aim 2 adopts a translational approach to address the utility of a recently discovered Kissir antagonist, peptide 234. This pharmacological agent has been shown to disrupt the neuroendocrine regulation of GnRH/LH secretion when injected into the cerebral ventricles; however, its ability to block central kisspeptin activity when administered outside of the blood-brain barrier has not been evaluated. I will test the efficacy of systemically administered peptide 234 in blocking the LH surge, disrupting the post- gonadectomy LH rise and estrous cyclicity, and preventing the onset of puberty. Relevance. Elucidating the significance of kisspeptin in the control of gonadotropin secretion may provide further insight into the mechanisms responsible for idiopathic hypogonadotropic hypogonadism. Moreover, this work with peptide 234 may establish the foundation for possible clinical treatments of reproductive disorders (e.g., precocious puberty, endometriosis, and metastatic prostate cancer). It is also conceivable that this knowledge might serve as the basis for the development of newer and better strategies for hormonal contraception (for both males and females) or ovulation induction.