The function of Runx1 in the ovary

描述（由申请人提供）： 本研究的目的是阐明核转录因子Runx 1在卵巢中的作用。我们最近发现，这种转录因子是显着和短暂的诱导颗粒细胞的排卵期卵泡后，LH [促黄体激素]激增。围排卵期卵泡经历了无数基因表达模式的快速变化，从而导致排卵和黄体化。因此，由LH峰诱导的转录调节因子被认为在排卵过程和黄体化中起重要作用。我们有初步的数据表明，LH诱导的Runx1在排卵期颗粒细胞中的表达的敲低导致孕酮的产生减少，涉及Runx1参与黄体化。我们还发现Runx1的表达受孕酮受体和EGF [表皮生长因子]受体的激活调节，这两种受体是已知的排卵过程的关键介质。基于这些新的发现，我们假设Runx1在排卵和黄体化中起重要作用。本提案的目的是：1）证明在排卵期颗粒细胞中诱导Runx 1对于成功排卵和黄体化至关重要，2）确定Runx 1在排卵期颗粒细胞中的特定作用。为了实现这一目标，我们将产生在颗粒细胞中特异性缺乏功能性Runx1的小鼠，然后检查这些突变小鼠的卵巢表型（特异性目标1）。使用颗粒细胞特异性Runx1基因敲除小鼠，我们将鉴定排卵期颗粒细胞中Runx1作用的下游基因（特异性目的2）。从这一建议中获得的信息将为排卵和黄体形成的机制提供新的见解。这些知识可以应用于促进或抑制卵巢生理学的这些关键方面，从而使我们能够更好地管理生育，不育和卵巢疾病。

DESCRIPTION (provided by applicant): The goal of the present proposal is to elucidate the role of Runx1, a nuclear transcription factor, in the ovary. We have recently identified that this transcription factor is dramatically and transiently induced in granulosa cells of periovulatory follicles after the LH [luteinizing hormone] surge. The periovulatory follicle undergoes rapid changes in the expression patterns of a myriad of genes to bring about ovulation and luteinization. Therefore, transcriptional regulators induced by the LH surge are believed to play an essential role in the ovulatory process and luteinization. We have preliminary data showing that knockdown of the LH-induced Runx1 expression in periovulatory granulosa cells resulted in a decrease in progesterone production, implicating the involvement of Runx1 in luteinization. We also found that Runx1 expression is regulated by the activation of the progesterone receptor and EGF [epidermal growth factor]-receptor, two known key mediators for the ovulatory process. Based on these novel findings, we hypothesize that Runx1 plays an important role(s) in ovulation and luteinization. The goal of this proposal is to: 1) demonstrate that the induction of Runx1 in periovulatory granulosa cells is essential for successful ovulation and luteinization and 2) determine the specific role(s) of Runx1 in periovulatory granulosa cells. To accomplish this goal, we will generate mice lacking functional Runx1 specifically in granulosa cells, and then examine the ovarian phenotype of these mutant mice (Specific Aim 1). Using the granulosa cell-specific Runx1 null mice, we will identify the genes down-stream of Runx1 action in periovulatory granulosa cells (Specific Aim 2). Information derived from this proposal will provide new insight into the mechanism(s) involved in ovulation and corpus luteum formation. Such knowledge can be applied for promoting or inhibiting these critical facets of ovarian physiology, thereby allowing us to better manage fertility, infertility, and ovarian-based disorders.