Endocrine and Paracrine Regulation of FSH Action in the Primary Ovary

原代卵巢中 FSH 作用的内分泌和旁分泌调节

• 批准号: 8053357
• 负责人: Anthony J Zeleznik
• 金额: $ 15.24万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8053357
• 关键词: Activins; Antral; Clinical Medicine; Contraceptive methods; Development; Differentiation and Growth; Drug Delivery Systems; Endocrine; GDF9 gene; Gonadotropins; Growth; Hand; Knowledge; Lead; Macaca; Methods; Modeling; Monkeys; Neoadjuvant Therapy; Oocytes; Ovarian; Ovarian Cycles; Ovary; Ovulation; Ovulation Induction; Physiology; Primates; Recombinant Activin; Recombinants; Regulation; Rodent; Role; Signal Transduction Pathway; Staging; System; Time; Woman; activin B; autocrine; cohort; folliculogenesis; granulosa cell; improved; in vivo; novel; paracrine

Significant progress has been made in understanding the roles of FSH and LH on the growth and differentiation of the preovulatory follicle in primates. Information gained from these studies has rapidly been assimilated into new strategies for ovulation induction in clinical medicine. A major question that remains unsolved is the elucidation of the control mechanisms that govern the early stages of follicular development, as well as the mechanisms by which these early follicles become responsive to FSH. Because preovulatory follicles must come from the pool of early developing follicles, knowledge of the physiology of preantral and early antral follicles is essential to further the understanding and our ability to manipulate the ovarian cycle. Because of their important roles in early follicular development in rodents and the documented expression of these factors and their signal transduction pathways at comparable stages of folliculogenesis in primates, we have chosen to study the effects the oocyte product, GDF-9, and the granulosa cell product, activin, on early follicular development in macaque monkeys. We will use a novel drug delivery system to deliver GDF-9 and activin B directly to ovaries in vivo in combination with our previously developed "gonadotropin clamp" model, which allows us to isolate local ovarian actions of autocrine/paracrine agents from systemic effects of these agents on gonadotropin secretion. This unique system will thus permit us to determine the local ovarian effects of these factors independently of systemic effects that have confused the results from previous studies. The Specific Aims of this revised project are: Specific Aim 1. To prepare and characterize recombinant GDF-9 and activin B for in vivo studies in monkeys. Specific Aim 2. To determine the effects of recombinant activin B on preantral follicular growth and on the responsiveness of the ovary to FSH and LH. Specific Aim 3. To determine the effects of recombinant GDF-9 on preantral follicular growth and on the responsiveness of the ovary to FSH and LH. An understanding of the regulation and development of early follicles in primates will lead to the possibility of therapies aimed at enhancing a cohort of follicles several cycles away from ovulation. In particular, in women who are "poor responders" to our current ovulation induction therapies, a larger and healthier cohort of early antral follicles at the time of gonadotropin treatment would likely improve both the quantity and quality of mature preovulatory follicles. On the other hand, knowledge of the factors that govern early follicular growth would facilitate the development of novel methods of fertility control.

在理解FSH和LH对生长和发育的作用方面取得了重大进展， 灵长类排卵前卵泡的分化。从这些研究中获得的信息迅速得到了 被吸收为临床医学中诱导排卵的新策略。仍然存在的一个主要问题 未解决的是阐明控制卵泡发育早期阶段的控制机制， 以及这些早期卵泡对FSH产生反应的机制。因为排卵前 卵泡必须来自早期发育的卵泡池，窦前和早期卵泡发育的生理学知识， 有腔卵泡对于进一步理解和操纵卵巢周期的能力是必不可少的。 由于它们在啮齿类动物早期卵泡发育中的重要作用， 在灵长类动物卵泡发生的可比较阶段， 我选择研究卵母细胞产物GDF-9和颗粒细胞产物激活素对早期妊娠的影响。 猕猴的卵泡发育。我们将使用一种新的药物输送系统来输送GDF-9， 结合我们先前开发的“促性腺激素钳夹”模型， 这使我们能够将自分泌/旁分泌因子的局部卵巢作用与这些因子的全身作用分开， 促性腺激素分泌的药物。这种独特的系统将使我们能够确定局部卵巢的影响， 这些因素的独立的系统性影响，混淆了从以前的研究结果。 这一修订项目的具体目标是： 具体目标1。制备并表征用于猴体内研究的重组GDF-9和激活素B。 具体目标2。为了确定重组激活素B对腔前卵泡生长的影响， 卵巢对FSH和LH的反应性。 具体目标3。为了确定重组GDF-9对腔前卵泡生长的影响， 卵巢对FSH和LH的反应性。 对灵长类动物早期卵泡的调节和发育的理解将导致这种可能性 旨在增强离排卵几个周期的卵泡群的疗法。特别是在妇女中， 对我们目前的促排卵疗法“反应不佳”的人， 促性腺激素治疗时的窦卵泡可能会改善成熟卵泡的数量和质量， 排卵前卵泡另一方面，了解影响早期卵泡生长的因素， 促进生育控制新方法的发展。