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）神经元在维持基底黄体激素（LH）分泌方面起着至关重要的作用，并且在产生排卵前的促性腺激素释放激素（GNRH）方面发挥了排卵所需的激增。该提案的总体目标是了解亲吻蛋白在调节繁殖中的生理功能，并评估其与发育和生殖疾病的避孕和治疗相关性。相应地，该提议分为两个具体目的，即1）解决性别分化的内卵腹脑周围核（AVPV）中的亲吻肽神经元（AVPV）的机制，通过促性腺固醇激活，以诱导预卵GNRH/LH振兴，并评估有可能的kisspectin forsist inspeptim inspeptim的潜在。具体而言，AIM 1将检验以下假设：AVPV的KISSI神经元中的孕酮受体（PR）信号在门控GNRH/LH激增中起重要作用。我将研究雌二醇（E2）的存在是否会在AVPV中的KISSI神经元中上调PR表达以及长期孕酮（P）治疗是否抑制KISSI神经元的激活，就像对GNRH/LH激增一样。此外，我将确定单独使用E2是否会引起每日激活Kissi。最后，我将确定功能性PR的存在对于仅E2反复激活Kissi神经元的能力至关重要。 AIM 2采用了一种转化方法来解决最近发现的Kissir拮抗剂肽234的实用性。当注射到脑室心室中时，该药理学剂已被证明会破坏GNRH/LH分泌的神经内分泌调节；但是，尚未评估其在血脑屏障外施用时阻断中央亲吻蛋白活性的能力。我将测试系统施用的肽234在阻断LH激增方面的功效，破坏后性腺切除术LH的上升和发情循环，并防止青春期的发作。关联。阐明亲吻肽在控制促性腺激素分泌方面的重要性可能会进一步深入了解负责特发性性低位核性低肿瘤的机制。此外，这项用肽234的工作可能为生殖疾病的可能临床治疗（例如早熟青春期，子宫内膜异位症和转移性前列腺癌）奠定基础。还可以想象，这些知识可能是发展荷尔蒙避孕（男性和女性）或排卵诱导的新策略的基础。