The MMP system in human ovulation: localization, regulation, and function

The preovulatory LH surge stimulates an increase in ovarian matrix metalloproteinases (MMPs) and their associated inhibitors, the TIMPs, (collectively referred to as the MMP system) prior to follicular rupture in many species. The paramount role of the MMP system in ovulation is forthcoming from numerous experiments where oocyte release is blocked by MMP inhibitors. Yet other than our preliminary data, nothing is known as to which MMPs and TIMPs are involved in the ovulatory process in the human. This question will be addressed in the first Specific Aim by using a unique model where the granulosa, theca, and stroma from human periovulatory follicles will be collected prior to and at three designated times after hCG. The expression patterns of key members of the MMP and TIMP family associated with follicular rupture in the human will be illuminated. Specific Aim #2 will build upon these observational findings and explore the regulation of these MMPs and TIMPs by known LH stimulated signaling pathways using well characterized models in the rodent and human. However, one of the key questions remains as to what are the MMPs and TIMPs actually doing during the process of follicular rupture? We propose that the ovarian MMP system directs the requisite proteolytic or “degradomic” changes necessary for ovulation. Thus, Specific Aim #3 will elucidate specific protein targets of MMP action by proteomic profiling allowing us to characterize the function of the MMPs and TIMPs in the ovulatory process. A major strength of this proposal is our extensive expertise with the MMP system that allows an integrated approach to understand the cellular expression, regulation, and impact of the MMP system on follicular ruture. One novel aspect of this study is the use of well characterized human preovulatory follicles as a foundation to explore the role of the MMP system in the process of human ovulation, which has never been accomplished. As such the proposed studies are extremely timely to elucidate the role that this exquisite proteolytic system plays in a key aspect of normal human ovarian physiology.