The overall goal of the proposed studies is to improve our understanding of the mechanisms by which human ovarian function is controlled by metalloproteinases and their inhibitors during the menstrual cycle. The proposal is based on the hypothesis that matrix metalloproteinases, as well as their associated inhibitors (i.e. tissue inhibitors of metalloproteinases, TIMPs), play a fundamental role in ovarian physiology by controlling extracellular matrix remodeling during follicular development, ovulation, and formation and regression of the corpus luteum (CL). The hypothesis to be tested is that there are dynamic, coordinated changes in the expression, activity, and cellular localization of metalloproteinases and their inhibitors which are regulated (both positively and negatively) by hormonal signals associated with these periods of extensive ovarian tissue remodeling. To test this hypothesis, the changes and regulation of enzyme and inhibitor will be determined during follicular development, ovulation, and CL function, using molecular, biochemical, morphologic, and physiologic techniques. The first specific aim will elucidate the cellular origin and determine the morphometric changes in ovarian metalloproteinases and TIMPs during follicular growth and luteal life span by in situ hybridization and immunohistochemistry. The second specific aim will determine the changes and regulation of collagenase, gelatinase, stromelysin, and TIMP mRNA and activity during the periovulatory and luteal periods. The regulation of enzyme and inhibitor by LH-induced messenger systems, such as prostaglandins, progesterone, and interleukins, will be studied in vitro with a granulosa or luteal cell culture model. The third specific aim will investigate the transcriptional regulation of gelatinase and TIMP expression by LH-induced messenger systems utilizing nuclear transcription run-on assays, DNA footprint analysis and promoter:reporter gene construct experiments. The fourth specific aim will determine the functional role of metalloproteinases and TIMPs by stimulating ovarian cells with exogenous TIMP or inhibiting TIMP action. The significance of these studies is in the applicability of the fundamental information obtained to promoting or inhibiting ovarian events controlled by metalloproteinase action (such as ovulation or CL formation) thereby leading to future applications for the improvement of fertility or contraception.
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