Kisspeptin signaling in the brain

描述（由申请人提供）：下丘脑中的Kisspeptin （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促性腺激素释放激素（GnRH）激增中起重要作用。本提案的总体目标是了解kisspeptin在生殖调节中的生理功能，并评估其与避孕和治疗发育和生殖障碍的相关性。相应地，本研究分为两个具体目标：1)研究性别分化前腹侧心室周围核（AVPV）中的kisspeptin神经元被性激素类固醇激活以诱导排卵前GnRH/LH激增的机制；2)评估kisspeptin拮抗剂的治疗潜力。具体来说，Aim 1将验证AVPV的Kissi神经元中的孕激素受体（PR）信号在控制GnRH/LH激增中起重要作用的假设。我将研究雌二醇（E2）的存在是否会上调AVPV中Kissi神经元中的PR表达，以及长期黄体酮(P)治疗是否会抑制Kissi神经元的激活，就像它对GnRH/LH激增的作用一样。此外，我将确定E2是否单独引起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Kissir拮抗剂肽234的效用。当注射到脑室时，这种药理学制剂已被证明会破坏GnRH/LH分泌的神经内分泌调节；然而，在血脑屏障外给药时，其阻断中枢kisspeptin活性的能力尚未得到评估。我将测试系统给药肽234在阻断黄体生成素激增、破坏性腺切除后黄体生成素上升和发情周期以及防止青春期开始方面的功效。的相关性。阐明kisspeptin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促性腺功能减退症的机制。此外，肽234的这项工作可能为生殖疾病（如性早熟、子宫内膜异位症和转移性前列腺癌）的临床治疗奠定基础。同样可以想象的是，这些知识可以作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.