HORMONE MEDIATED REGULATION OF OVARIAN FUNCTION

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. This project explores estrogen action on the ovary and the mammary gland. Studies conducted during the past funding period have explored the changes in 1) the ovarian matrix metalloproteinases, 2) ovarian gene expression, and 3) a class of nuclear hormone receptors, the peroxisome proliferator-activated receptors (PPARs), in mammary gland function. All four of the investigators associated with this project have made significant progress towards their individual experiments as well as towards establishing preliminary data for the competitive renewal of this Project. Dr. Misung Jo is continuing to examine the functional significance of a novel gene, Runx1, in late follicle development. The localization pattern of Runx1 expression and the mechanism(s) of Runx1 expression continue to shed light on the functional role this protein plays in follicular development and ovulation. Preliminary experiments with silencing RNA have suggested that Runx1 may mediate the LH induced increase in progesterone production. Experiments by Dr. Michael Kilgore have continued to investigate the signal crosstalk between the estrogen receptor beta (ERb) and the peroxisome proliferator-activated receptor gamma (PPARg). Preliminary data indicates that crosstalk between these receptors results in gene-specific changes with a number of genes being upregulated while other genes are downregulated as seen by DNA microarray. Ongoing studies are examining the significance of these changes in gene expression on cellular proliferation and migration. Finally, a series of breeding experiments by Dr. Jay Ko have been in progress to generate tissue-specific knockouts of the estrogen receptor (ER) isoforms. These ongoing studies are creating mice which lack ERa or ERb in the oocyte, the granulosa cell, or the theca cells. To date, oocyte-specific estrogen receptor knockout have been generated which lack ERa. These mice exhibit a reduced ovulatory capacity although they are fertile. The impact of estrogen action on the theca and granulosa cell layers of the follicle will be explored as these mice become available. In Dr. Curry's laboratory, the role and timing of expression of the matrix metalloproteinase-19 and its inhibitors in ovarian development and ovulation continues to be unraveled. These studies demonstrate the importance of tissue remodeling in regulating ovarian function and fertility. Therefore, all the projects have made significant progress in developing the necessary tools to address the goals of each project and are in an excellent position to provide convincing data for the competitive renewal of the COBRE project as well as compete for extramural support.