The function of Runx1 in the ovary

描述（由申请人提供）：本提案的目的是阐明Runx1，一种核转录因子，在卵巢中的作用。我们最近发现，在促黄体生成素激增后，这种转录因子在排卵卵泡颗粒细胞中被显著和短暂地诱导。排卵卵泡经历快速变化的表达模式的无数基因带来的排卵和黄体化。因此，由黄体生成素激增诱导的转录调节因子被认为在排卵过程和黄体生成中起重要作用。我们有初步的数据显示，在排卵周颗粒细胞中，敲低lh诱导的Runx1表达导致孕酮产生减少，暗示Runx1参与黄体生成。我们还发现Runx1的表达受黄体酮受体和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。基于这些新发现，我们假设Runx1在排卵和黄体生成中起重要作用。本研究的目的是：1)证明Runx1在排卵期颗粒细胞中的诱导对成功排卵和黄体生成至关重要；2)确定Runx1在排卵期颗粒细胞中的具体作用。为了实现这一目标，我们将在颗粒细胞中产生特异性缺乏Runx1功能的小鼠，然后检测这些突变小鼠的卵巢表型（Specific Aim 1）。使用颗粒细胞特异性Runx1缺失小鼠，我们将在排卵期颗粒细胞中鉴定Runx1作用的下游基因（Specific Aim 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，不孕症和卵巢疾病。

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.