Kisspeptin signaling in the brain

描述（由申请方提供）：下丘脑中的Kisspeptin（Kissi）神经元在维持基础促黄体生成素（LH）分泌和产生排卵所需的排卵前促性腺激素释放激素（GnRH）峰方面发挥重要作用。该提案的总体目标是了解kisspeptin在生殖调节中的生理功能，并评估其与避孕以及治疗发育和生殖障碍的相关性。相应地，该提议分为两个具体目标，1）解决性分化的前腹侧室周核（AVPV）中kisspeptin神经元被性腺类固醇激活以诱导排卵前GnRH/LH峰的机制，以及2）评估kisspeptin拮抗剂的治疗潜力。具体来说，目标1将测试的假设，孕激素受体（PR）信号在AVPV的Kissi神经元在门控GnRH/LH浪涌起着重要作用。我将研究雌二醇（E2）的存在是否上调PR表达在Kissi神经元的AVPV和长期孕酮（P）治疗是否抑制Kissi神经元的激活，就像它对GnRH/LH浪涌。此外，我将确定是否E2单独eliminate日常激活Kissi。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。目的2采用翻译的方法来解决最近发现的Kissir拮抗剂，肽234的效用。该药理学药物已被证明在注射入脑室时会破坏GnRH/LH分泌的神经内分泌调节;然而，尚未评价其在血脑屏障外给药时阻断中枢kisspeptin活性的能力。我将测试全身施用肽234在阻断LH峰、破坏性腺切除术后LH升高和发情周期以及预防青春期开始方面的功效。本案无关阐明kisspeptin在控制促性腺激素分泌中的重要性可能为特发性低促性腺激素性性腺功能减退症的机制提供进一步的见解。此外，肽234的这项工作可能为生殖疾病的可能临床治疗奠定基础（例如，性早熟、子宫内膜异位症和转移性前列腺癌）。也可以想象，这一知识可能成为开发更新和更好的激素避孕（男性和女性）或排卵诱导策略的基础。

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.