Hormonal Signals that Regulate Ovarian Diffrentiation

描述（由申请人提供）：该提案要求西北大学P01计划“调节卵巢分化的激素信号”的21-25年延期。该计划在生殖科学领域有着悠久的合作发现研究历史，在资助的整个生命周期内取得了许多科学突破。该计划的主要主题是研究激素或其他调节因子作用于卵巢的信号通路，以促进类固醇生成以及维持女性生育能力所需的卵泡和生殖细胞的成熟。为了研究这一主题，我们提出了3个新的研究项目，这些项目代表了我们在上一次资助期间取得的进展和我们最近的初步发现所激发的新颖和创造性的研究方向。项目1（Kelly马约和Teresa Woodruff）专注于卵巢发育和调节生殖细胞巢分解以形成原始卵泡初始池的事件。这些研究使用新的方法来研究Notch信号传导，激活素作用和雌激素调节导致卵泡形成的作用。项目2（乔恩·莱文， Larry Jameson，Jeff韦斯）研究了卵泡生长的后期阶段，重点是通过卵巢内以及卵巢和下丘脑-垂体轴之间的非经典ER α途径的雌激素信号传导。这些研究使用创造性的方法来剖析大脑和卵巢中对生殖功能至关重要的ER α信号传导机制。项目3（Teresa Woodruff，Tom O 'Halloran）探索卵泡和卵母细胞成熟的最后阶段，并研究无机信号分子和过渡金属锌及其在女性生殖细胞中的作用。这些实验在化学-生物学界面上应用了令人兴奋的方法，以更好地理解卵母细胞成熟的调节。行政核心和卵巢组织学核心提供支持，促进3个科学项目的研究。这个高度互动的调查团队的集体优势允许思想和研究合作的协同作用，这将确保我们的进展远远超出任何单个项目的限制，并捕捉P01计划机制的全部优势。初始卵泡池的建立、卵泡功能和类固醇生成的控制以及雌性生殖细胞的成熟是生殖研究中的关键问题，这些问题定义了该计划的中心主题。这些问题对于改善影响生育力的疾病和功能障碍的诊断、理解和治疗也具有根本重要性，因此与人类健康直接相关。我们期望P01计划提案中提出的基础研究项目将产生相当大的影响，最终导致人类生殖健康的改善。

DESCRIPTION (provided by applicant): This proposal requests renewal for years 21-25 of the P01 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 hypothalamic-pituitary 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 P01 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.