The preovulatory LH surge stimulates an increase in ovarian extracellular matrix metalloproteinase inducer (EMMPRIN), which is known as a classic regulator o fthe matrix metalloproteinases (MMPs). The paramount role of EMMPRIN in ovulation is evident from experiments in mice lacking EMMPRIN that display a decrease in oocyte release and fertilization. Yet other than our preliminary data, nothing is known as to temporal expression patterns, the regulation, and potential function of EMMPRIN in the ovulatory process in the human. This question will be addressed in the proposed POI program through a collaborative approach utilizing the exceptional backgrounds, technical expertise, and models ofthe PIs. We will make use of a unique model where the granulosa and theca from human periovulatory follicles will be collected prior to and at three designated times after hCG (early, late and postovulatory). The expression patterns of EMMPRIN in the human will be illuminated in Aim #1.
Specific Aim #2 will build upon these findings to elucidate the role of EMMPRIN in ovarian angiogenesis in the human, macaque and rat. The ability of EMMPRIN to stimulate proliferation, migration and spouting of new vessels will be determined. To further characterize EMMPRIN's action.
Specific Aim #3 will investigate the role of EMMPRIN in immune cell trafficking'Specifically, studies will explore the impact of EMMPRIN on leukocyte expression of the MMP system and EMMPRIN's ability to regulate the invasive capacity of leukocytes. One novel aspect of this study is the use of well characterized human preovulatory follicles as a foundation to explore the expression and function of EMMPRIN in the process of human ovulation, which has never been accomplished. Another major strength of this proposal is the collaborative interactions between different investigators to address the function of EMMPRIN in periovulatory events across multiple species. 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 use human tissues collected at carefully defined times prior to and immediately after ovulation to investigate the changes in gene expression patterns that may impact oocyte release. The changes in these genes and their regulation will be studied using both human tissues and rodent models to mimic the human. These studies will expand our understanding of ovulation in the human.
|Cacioppo, Joseph A; Lin, Po-Ching Patrick; Hannon, Patrick R et al. (2017) Granulosa cell endothelin-2 expression is fundamental for ovulatory follicle rupture. Sci Rep 7:817|
|Puttabyatappa, Muraly; Al-Alem, Linah F; Zakerkish, Farnosh et al. (2017) Induction of Tissue Factor Pathway Inhibitor 2 by hCG Regulates Periovulatory Gene Expression and Plasmin Activity. Endocrinology 158:109-120|
|Choi, Yohan; Wilson, Kalin; Hannon, Patrick R et al. (2017) Coordinated Regulation Among Progesterone, Prostaglandins, and EGF-Like Factors in Human Ovulatory Follicles. J Clin Endocrinol Metab 102:1971-1982|
|Kim, Soon Ok; Trau, Heidi A; Duffy, Diane M (2017) Vascular endothelial growth factors C and D may promote angiogenesis in the primate ovulatory follicle. Biol Reprod 96:389-400|
|Cacioppo, Joseph A; Koo, Yongbum; Lin, Po-Ching Patrick et al. (2016) Generation of an estrogen receptor beta-iCre knock-in mouse. Genesis 54:38-52|
|Cerny, Katheryn L; Ribeiro, Rosanne A C; Jeoung, Myoungkun et al. (2016) Estrogen Receptor Alpha (ESR1)-Dependent Regulation of the Mouse Oviductal Transcriptome. PLoS One 11:e0147685|
|Oakley, Oliver R; Kim, Kee Jun; Lin, Po-Ching et al. (2016) Estradiol Synthesis in Gut-Associated Lymphoid Tissue: Leukocyte Regulation by a Sexually Monomorphic System. Endocrinology 157:4579-4587|
|Trau, Heidi A; Brännström, Mats; Curry Jr, Thomas E et al. (2016) Prostaglandin E2 and vascular endothelial growth factor A mediate angiogenesis of human ovarian follicular endothelial cells. Hum Reprod 31:436-44|
|Wilson, Kalin; Park, Jiyeon; Curry Jr, Thomas E et al. (2016) Core Binding Factor-? Knockdown Alters Ovarian Gene Expression and Function in the Mouse. Mol Endocrinol 30:733-47|
|Kim, Soon Ok; Duffy, Diane M (2016) Mapping PTGERs to the Ovulatory Follicle: Regional Responses to the Ovulatory PGE2 Signal. Biol Reprod 95:33|
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