Kisspeptin signaling in the brain

Kisspeptin 大脑中的信号传导

• 批准号: 8065883
• 负责人: Amy Elizabeth Oakley
• 金额: $ 5.13万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8065883
• 关键词: 17p; Address; Adopted; Blood - brain barrier anatomy; Brain; Cell Nucleus; Cerebral Ventricles; Clinical Treatment; Contraceptive methods; Development; Disease; Down-Regulation; Estradiol; Estrogen Receptor alpha; Estrus; Female; Foundations; Genes; Goals; Gonadal Steroid Hormones; Gonadotropin Hormone Releasing Hormone; Gonadotropins; Human; Hypothalamic structure; KISS1R gene; Kallmann Syndrome; Klinefelter' s Syndrome; Knowledge; Luteinizing Hormone; Maintenance; Metastatic Prostate Cancer; Methods; Molecular; Mus; Neurons; Neurosecretory Systems; Ovulation; Ovulation Induction; Pathway interactions; Peptides; Periodicity; Physiological; Play; Precocious Puberty; Prevention; Production; Progesterone; Progesterone Receptors; Puberty; Receptor Signaling; Regulation; Reproduction; Research; Rodent; Role; Signal Transduction; Testing; Therapeutic; Work; base; critical period; design; efficacy testing; endometriosis; hormonal contraception; insight; kisspeptin; loss of function mutation; mRNA Expression; male; prevent; receptor; receptor expression; reproductive; reproductive axis; tool; translational approach

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.

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排卵前促性腺激素释放激素 (GnRH) 激增方面发挥着重要作用。该提案的首要目标是了解 Kisspeptin 在生殖调节中的生理功能，并评估其与避孕以及发育和生殖障碍治疗的相关性。相应地，该提案分为两个具体目标：1）解决性别分化的前腹室周围核（AVPV）中的 Kisspeptin 神经元被性腺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，目标 1 将检验以下假设：AVPV Kissi 神经元中的孕酮受体 (PR) 信号在门控 GnRH/LH 激增中发挥重要作用。我将研究雌二醇 (E2) 的存在是否上调 AVPV 中 Kissi 神经元的 PR 表达，以及长期孕酮 (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 的存在是否对于 E2 单独重复激活 Kissi 神经元的能力至关重要。目标 2 采用转化方法来解决最近发现的 Kissir 拮抗剂肽 234 的效用。该药物已被证明在注射到脑室时会破坏 GnRH/LH 分泌的神经内分泌调节；然而，其在血脑屏障外给药时阻断中枢 Kisspeptin 活性的能力尚未得到评估。我将测试全身施用肽 234 在阻止 LH 激增、破坏性腺切除术后 LH 升高和动情周期以及预防青春期开始方面的功效。关联。阐明 Kisspeptin 在控制促性腺激素分泌中的重要性可能有助于进一步了解特发性低促性腺激素性性腺功能减退症的机制。此外，这项针对肽 234 的研究可能为生殖疾病（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。还可以想象，这些知识可以作为开发更新更好的激素避孕（男性和女性）或促排卵策略的基础。