The Function of Runx1 in the Ovary

Principal Investigator/Program Director (Last, First, Middle): Jo, Misung DESCRIPTION: See instructions. State the application's broad, long-term objectives and specific aims, making reference to the health relatedness of the project (i.e., relevance to the mission of the agency). Describe concisely the research design and methods for achieving these goals. Describe the rationale and techniques you will use to pursue these goals. In addition, in two or three sentences, describe in plain, lay language the relevance of this research to public health. If the application is funded, this description, as is, will become public information. Therefore, do not include proprietary/confidential information. DO NOT EXCEED THE SPACE PROVIDED. 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 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-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 peri ovulatory 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. PERFORMANCE SITE(S} (organization, city, state) Department of Obstetrics & Gynecology Chandler Medical Center College of Medicine University of Kentucky Lexington, KY 40536-0293 PHS 398 (Rev. 09/04) Page ~ Form Page 2