Hormonal Signals that Regulate Ovarian Diffrentiation

该提案要求更新21-25年的POI计划“激素信号，调节 卵巢分化”在西北大学。该计划有着悠久的合作历史， 在生殖科学领域进行的基于发现的研究，导致了许多科学突破 在补助金的有效期内该计划的主要主题是调查信号通路， 激素或其它调节因子作用于卵巢以促进类固醇生成和 维持女性生育能力所必需的卵泡和生殖细胞。为了研究这一主题，3项新的研究 项目提出，代表新颖和创造性的研究方向，灵感来自我们的进展， 最后一次拨款和我们最近的初步调查结果。项目1（凯利马约和特蕾莎 Woodruff）专注于卵巢发育和调控生殖细胞巢破裂的事件， 形成原始卵泡的初始池。这些研究使用新的方法来研究Notch的作用 信号传导、激活素作用和雌激素调节导致卵泡形成。项目2（乔恩·莱文， Larry Jameson，Jeff韦斯）研究卵泡生长的后期阶段，重点是雌激素信号 通过卵巢内和卵巢与下丘脑-垂体之间的非经典ER α通路 轴线这些研究使用创造性的方法来剖析ER α信号转导机制， 大脑和卵巢对生殖功能至关重要。项目3（特蕾莎伍德拉夫，汤姆奥哈洛伦）探索 卵泡和卵母细胞成熟的最后阶段，并研究了无机信号分子， 过渡金属锌及其在女性生殖细胞中的作用。这些实验应用于令人兴奋的 在化学-生物学界面的方法，以更好地了解卵母细胞成熟的调节。一个 行政核心和卵巢组织学核心提供支持，促进在3 科学项目。这个高度互动的调查小组的集体力量允许产生协同作用 的想法和研究合作，这将确保我们的进展远远超出任何限制， 单个项目，并充分利用POI计划机制的优势。成立 最初的卵泡池，卵泡功能和类固醇生成的控制，以及雌性生殖细胞的成熟， 生殖研究中的关键问题，确定了这个计划的中心主题。这些问题也 对改进疾病的诊断、理解和治疗具有根本重要性， 生殖系统功能障碍影响生育力，因此与人类健康直接相关。我们期望 P01计划建议中提出的基础研究项目最终将产生相当大的影响， 从而改善人类生殖健康。

This proposal requests renewal for years 21-25 of the POl program "Hormonal Signals that Regulate Ovarian Differentiation" at Northwestern University. The program has a long history of collaborative discovery-based research in the reproductive sciences that has led to numerous scientific breakthroughs over the lifetime of the grant. The major theme of the program is to investigate signaling pathways by which hormones or other regulatory factors act on the ovary to promote steroidogenesis and the maturation of follicles and germ cells necessary to sustain female fertility. To investigate this theme, 3 new research projects are proposed that represent novel and creative research directions inspired by our progress during the last grant period and by our most recent preliminary findings. Project 1 (Kelly Mayo and Teresa Woodruff) focuses on ovarian development and the events that regulate the breakdown of germ cell nests to form the initial pool of primordial follicles. These studies use novel approaches to investigate roles for Notch signaling, activin action and estrogen regulation leading to ovarian follicle formation. Project 2 (Jon Levine, Larry Jameson, Jeff Weiss) examines later stages of follicle growth, with an emphasis on estrogen signaling through non-classical ERa pathways both within the ovary and between the ovary and the hypothalamicpituitary axis. These studies use creative approaches to dissect mechanisms of ERa signaling in both the brain and the ovary critical to reproductive function. Project 3 (Teresa Woodruff, Tom O'Halloran) explores the final stages of follicle and oocyte maturation and investigates the inorganic signaling molecule and transition metal zinc and its actions within the female germ cell. These experiments apply exciting approaches at the chemical-biology Interface to better understand the regulation of oocyte maturation. An Administrative Core and an Ovarian Histology Core provide support that facilitates the research in the 3 scientific projects. The collective strengths of this highly interactive investigative team allow for a synergism of ideas and research collaborations that will ensure that we progress well beyond the limitations of any individual project and capture the full advantages of the POl program mechanism. Establishment of the initial follicle pool, control of follicle function and steroidogenesis, and maturation of the female germ cell are critical issues in reproductive research that define the central theme of this program. These issues are also of fundamental importance to improving the diagnosis, understanding and treatment of diseases and dysfunctions impacting fertility, and thus are of direct relevance to human health. It is our expectation that the basic research projects presented in this P01 program proposal will have considerable impact, ultimately leading to improvements in human reproductive health.