The function of Runx1 in the ovary

描述(申请人提供)：本提案的目的是阐明核转录因子RUNX1在卵巢中的作用。我们最近发现，在黄体生成素激增后，这种转录因子在排卵周卵泡的颗粒细胞中被戏剧性地和瞬时地诱导。排卵周卵泡经历了大量基因表达模式的快速变化，从而导致排卵和黄体化。因此，由黄体生成素高峰诱导的转录调节被认为在排卵过程和黄体化过程中起着重要的作用。我们已有的初步数据表明，在排卵周围颗粒细胞中，通过抑制促黄体生成素RUNX1的表达，导致孕酮的产生减少，暗示RUNX1参与了黄体生成。我们还发现，RUNX1的表达受孕激素受体和EGF受体的激活调节，这两种受体是排卵过程中的两个已知关键介质。基于这些新的发现，我们推测RUNX1在排卵和黄体化中起重要作用(S)。这项建议的目的是：1)证明RUNX1在排卵周围颗粒细胞中的诱导对于成功排卵和黄体化是必不可少的；2)确定RUNX1在排卵周围颗粒细胞中的特定作用(S)。为了实现这一目标，我们将产生颗粒细胞中缺乏功能性RUNX1的小鼠，然后检查这些突变小鼠的卵巢表型(特定目标1)。利用颗粒细胞特异性RUNX1缺失小鼠，我们将确定排卵周围颗粒细胞中RUNX1作用的下游基因(特定目标2)。从这一建议中获得的信息将为了解排卵和黄体形成的机制(S)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.