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 progression and temporal patterns of the MMPs and TIMPs 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 (early, late and postovulatory). 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 rupture. 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 the coordinated processes of follicular rupture and oocyte release which are key aspects of normal human ovarian physiology.
The proposed studies will investigate the underlying mechanism involved in human ovulation, which is a process where the egg is released from the follicle in the ovary. These studies will focus on a family of proteolytic enzymes, known as metalloproteinases, that we believe breakdown the wall of the ovarian follicle to allow the egg to be released. Only by fully understanding such basic tenets of ovarian function will we be able to promote or inhibit the events associated with metalloproteinase action during the ovulatory process thereby facilitating and increasing fertility or acting in a contraceptive manner to decrease fertility.
|Al-Alem, Linah; Puttabyatappa, Muraly; Rosewell, Kathy et al. (2015) Chemokine Ligand 20: A Signal for Leukocyte Recruitment During Human Ovulation? Endocrinology 156:3358-69|
|Rosewell, Katherine L; Al-Alem, Linah; Zakerkish, Farnosh et al. (2015) Induction of proteinases in the human preovulatory follicle of the menstrual cycle by human chorionic gonadotropin. Fertil Steril 103:826-33|
|Al-Alem, Linah; Curry Jr, Thomas E (2015) Ovarian cancer: involvement of the matrix metalloproteinases. Reproduction 150:R55-64|
|Rosewell, Katherine L; Li, Feixue; Puttabyatappa, Muraly et al. (2013) Ovarian expression, localization, and function of tissue inhibitor of metalloproteinase 3 (TIMP3) during the periovulatory period of the human menstrual cycle. Biol Reprod 89:121|
|Al-Alem, Linah F; McCord, Lauren A; Southard, R Chase et al. (2013) Activation of the PKC pathway stimulates ovarian cancer cell proliferation, migration, and expression of MMP7 and MMP10. Biol Reprod 89:73|
|McCord, Lauren A; Li, Feixue; Rosewell, Katherine L et al. (2012) Ovarian expression and regulation of the stromelysins during the periovulatory period in the human and the rat. Biol Reprod 86:78|
|Li, Feixue; Jang, Hyein; Puttabyatappa, Muraly et al. (2012) Ovarian FAM110C (family with sequence similarity 110C): induction during the periovulatory period and regulation of granulosa cell cycle kinetics in rats. Biol Reprod 86:185|
|Li, Feixue; Jo, Misung; Curry Jr, Thomas E et al. (2012) Hormonal induction of polo-like kinases (Plks) and impact of Plk2 on cell cycle progression in the rat ovary. PLoS One 7:e41844|
|Rosewell, Katherine; Al-Alem, Linah; Li, Feixue et al. (2011) Identification of hepsin and protein disulfide isomerase A3 as targets of gelatinolytic action in rat ovarian granulosa cells during the periovulatory period. Biol Reprod 85:858-66|
|Li, Feixue; Liu, Jing; Jo, Misung et al. (2011) A role for nuclear factor interleukin-3 (NFIL3), a critical transcriptional repressor, in down-regulation of periovulatory gene expression. Mol Endocrinol 25:445-59|
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