Reversible Contraception by Selective Silencing of GnRH-II

通过选择性沉默 GnRH-II 实现可逆避孕

• 批准号: 9908147
• 负责人: HENRYK F URBANSKI
• 金额: $ 63.87万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-15 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9908147
• 关键词: Active Immunization; Adult; Anatomy; Animal Model; Animals; Anterior Pituitary Gland; Biological Assay; Biological Models; Blood Circulation; Blood specimen; Brain; Contraceptive Agents; Contraceptive methods; Control Animal; Data; Development; Disease; Endocrine; Estradiol; Estrogens; Etiology; Exposure to; Feedback; Female; Female Contraceptive Agents; Fertility Study; Foundations; GNRH1 gene; Germ Cells; Goals; Gonadal Steroid Hormones; Gonadotropin Hormone Releasing Hormone; Gonadotropins; Growth and Development function; Histology; Hormones; Human; Hypothalamic structure; Immunization; Immunize; Infertility; Link; Location; Macaca mulatta; Maintenance; Mediating; Menstrual cycle; Menstruation; Modeling; Molecular; Monitor; National Institute of Child Health and Human Development; Neurons; Neuropeptides; Neurosecretory Systems; Ovarian; Ovariectomy; Ovary; Ovulation; Pattern; Phase; Play; Population; Primates; Production; Progesterone; Reproductive Physiology; Research; Research Priority; Rest; Safety; Steroid biosynthesis; Steroids; Testing; Tupaiidae; Ultrasonography; base; contraceptive target; corpus luteum; human female; innovative technologies; insight; mullerian-inhibiting hormone; negative affect; nonhuman primate; novel; novel strategies; proliferative phase Menstrual cycle; receptor; reproductive; reproductive axis; reproductive hormone; response; therapy development

PROJECT SUMMARY The overall goal of this proposal is to upgrade our understanding of the primate neuroendocrine reproductive axis, and thereby to lay a foundation for the development of novel contraceptives and to gain new insights about the etiology of idiopathic human reproductive disorders. This goal is thus responsive to one of NICHD's new Research Priorities: “To Encourage the Development of Innovative Technologies and Model Systems to Study Fertility and Infertility.” Specifically, the proposed research will empirically test the hypothesis that active immunization against GnRH-II can provide safe and effective long-term contraception - by selectively silencing the LH surge mechanism, while leaving the rest of the neuroendocrine reproductive axis intact. In humans, gonadotropin-releasing hormone (GnRH) neurons represent the primary neuroendocrine link between the brain and the rest of the reproductive axis, yet the mechanism by which these neurons trigger ovulation is poorly understood. Recently, however, human and rhesus macaques (but not rodents) were found to express two different molecular forms of GnRH (GnRH-I and GnRH-II). Furthermore, only the GnRH-II neurons were found to respond positively to estrogen feedback, suggesting that GnRH-II neurons serve as the primary trigger of the mid-cycle preovulatory LH surge. We therefore hypothesize that selective silencing of GnRH-II neurons will block ovulation without perturbing ovarian steroidogenesis or affecting negative feedback of estrogen on GnRH-I neurons. This hypothesis will be empirically tested using the female rhesus macaque, a highly translational nonhuman primate animal model that shows human-like menstrual cycles and similar organization of its reproductive neuroendocrine axis. Specific Aim 1: To test the hypothesize that active immunization against GnRH-II will selectively block ovulation without impacting ovarian steroidogenesis. We will test this hypothesis by immunizing adult female rhesus macaques against unique non-conserved regions of the GnRH-II neuropeptide; control animals will be immunized against a unique non-conserved region of GnRH- I. After immunization, the animals will be examined daily for signs of menstruation and circulating levels of reproductive hormones (i.e., LH, FSH, estradiol, progesterone, anti-Müllerian hormone) will be monitored in bi- weekly blood samples. We expect to show that selective immunization against GnRH-II will block development of the mid-cycle LH surge and corpus luteum formation (i.e., inferred by maintenance of low circulating progesterone levels). Specific Aim 2: To elucidate the neuroendocrine mechanism that underlies the contraceptive potential of GnRH-II silencing. Using remote serial blood sampling we will examine the dynamic relationships between reproductive hormone levels in the circulation after immunization (1) in ovary-intact animals, (2) after ovariectomy, and (3) after estrogen induction of an LH surge. We expect to show that selective silencing of GnRH-II will completely block the positive estrogen feedback component of the neuroendocrine reproductive axis, while leaving the GnRH-I-mediated negative feedback component functionally intact.

项目摘要 该提案的总体目标是提高我们对灵长类神经内分泌复制品的理解 轴心，从而为开发新型避孕药并获得新见解奠定了基础 关于特发性人类生殖疾病的病因。因此，这个目标是对NICHD的一个响应 新的研究优先事项：“鼓励开发创新技术和模型系统 研究的生育能力和不育。”具体而言，拟议的研究将紧急检验活性的假设 对GNRH-II的免疫可以通过选择性沉默可以提供安全有效的长期避孕 LH激发机制，同时离开其余的神经内分泌复制轴完整。 在人类中，促性腺激素释放激素（GNRH）神经元代表主要神经内分泌链接 在大脑和其余生殖轴之间，这些神经元触发的机制 排卵知之甚少。然而，最近发现了人类和恒河猕猴（但未发现啮齿动物） 表达两种不同的分子形式的gnRH（gnRH-i和gnRH-ii）。此外，只有gnrh-ii 发现神经元对雌激素反馈的反应积极，表明GnRH-II神经元充当 中期循环前LH激增的主要触发因素。因此，我们假设选择性沉默 GnRH-II神经元将阻止排卵而不会扰动卵巢类固醇生成或影响负反馈 GnRH-I神经元上的雌激素。该假设将使用雌性恒河猕猴进行经验检验 高度翻译的非人类灵长类动物模型，显示人类的月经周期和类似 其生殖神经内分泌轴的组织。特定目的1：测试假设的活动 针对GNRH-II的免疫将有选择地阻断排卵，而不会影响卵巢类固醇生成。我们 将通过对成年雌性恒河猕猴进行免疫侵害独特的非保守区域来检验这一假设 GNRH-II神经肽；对照动物将针对独特的GNRH-独特的非保守区域进行免疫 I.免疫后，将每天检查动物的月经和循环水平 将在Bi-中监测生殖骑术（即LH，FSH，雌二醇，孕酮，孕酮，抗肿瘤） 每周的血液样本。我们希望证明针对GNRH-II的选择性免疫将阻止发展 中循环LH潮和曲肠曲构的形成（即，通过维持低循环来推断 孕酮水平）。具体目的2：阐明基础的神经内分泌机制 GnRH-II沉默的避孕潜力。使用远程系列血液采样，我们将检查动态 免疫后循环中的复制骑士水平之间的关系（1） 动物，（2）卵巢切除术后和（3）LH激增后雌激素诱导后。我们希望证明这种选择性 GNRH-II的沉默将完全阻止神经内分泌的阳性雌激素反馈成分 生殖轴，同时离开GNRH-I介导的负反馈组件在功能上完整。