Ovulation is essential for successful reproduction. The ovulatory luteinizing hormone surge stimulates perieovulatory follicles to produce prostaglandin E2 (PGE2), which is required for expansion of the cumulus granulosa cells, follicle rupture, and oocyte release. Blockade of PGE2 production causes ovulation failure, supporting investigation of PGE2 as a treatment for infertility as well as inhibition of PGE2 synthesis/action as a potential contraceptive. To unravel the mechanism by which PGE2 stimulates perieovulatory events, this proposal puts forth the overall hypothesis that each of the four PGE2 (EP) receptors has a unique function in ovulation. First, we will determine which EP receptors are expressed by functionally-distinct subpopulations of granulosa cells within perieovulatory follicles. Using laser capture microdissection as well as immunofluorescent EP detection in monkey ovarian tissue sections, we will identify the EP receptor(s) present in cumulus, basal mural, and antral mural granulosa cells as well as granulosa cells located at the follicle apex. These subpopulations each play a unique role in ovulation, and we anticipate that each subpopulation expresses a unique subset of all EP receptors. Second, we will demonstrate that each EP receptor mediates a subset of all PGE2-stimulated preovulatory processes. PGE2 is known to stimulate granulosa cell progesterone production, cumulus expansion, and follicle rupture. Granulosa cell cultures as well as intrafollicular injection in macaques will be utilized to demonstrate that agonists specific for each EP receptor stimulate some, but not all, of these essential PGE2-mediated granulosa cell functions. Finally, we will determine which EP receptors can transduce the PGE2 signal in granulosa cells of primate preovulatory follicles. Granulosa cells will be treated with agonists specific for each of the four EP receptors, and intracellular signals generated via these G protein coupled receptors will be assessed. Each EP receptor will likely respond to agonist stimulation with a unique intracellular response. The proposed studies will likely demonstrate that each EP receptor mediates a specific subset of the total preovulatory response to PGE2 within the primate follicle. These data will facilitate a targeted pharmacological approach to selectively stimulate or inhibit essential features of the ovulatory process and may ultimately lead to the development of new treatments for infertility and novel contraceptive options.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
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Integrative and Clinical Endocrinology and Reproduction Study Section (ICER)
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Taymans, Susan
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Eastern Virginia Medical School
Schools of Medicine
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Kim, Soon Ok; Duffy, Diane M (2016) Mapping PTGERs to the Ovulatory Follicle: Regional Responses to the Ovulatory PGE2 Signal. Biol Reprod 95:33
Duffy, Diane M (2015) Novel contraceptive targets to inhibit ovulation: the prostaglandin E2 pathway. Hum Reprod Update 21:652-70
Trau, Heidi A; Davis, John S; Duffy, Diane M (2015) Angiogenesis in the primate ovulatory follicle is stimulated by luteinizing hormone via prostaglandin E2. Biol Reprod 92:15
Kim, Soon Ok; Markosyan, Nune; Pepe, Gerald J et al. (2015) Estrogen promotes luteolysis by redistributing prostaglandin F2? receptors within primate luteal cells. Reproduction 149:453-64
Stilley, Julie A; Guan, Rongbin; Duffy, Diane M et al. (2014) Signaling through FSH receptors on human umbilical vein endothelial cells promotes angiogenesis. J Clin Endocrinol Metab 99:E813-20
Puttabyatappa, Muraly; Jacot, Terry A; Al-Alem, Linah F et al. (2014) Ovarian membrane-type matrix metalloproteinases: induction of MMP14 and MMP16 during the periovulatory period in the rat, macaque, and human. Biol Reprod 91:34
Kim, Soon Ok; Harris, Siabhon M; Duffy, Diane M (2014) Prostaglandin E2 (EP) receptors mediate PGE2-specific events in ovulation and luteinization within primate ovarian follicles. Endocrinology 155:1466-75
Kim, Soon Ok; Dozier, Brandy L; Kerry, Julie A et al. (2013) EP3 receptor isoforms are differentially expressed in subpopulations of primate granulosa cells and couple to unique G-proteins. Reproduction 146:625-35
Harris, Siabhon M; Aschenbach, Lindsey C; Skinner, Stephanie M et al. (2011) Prostaglandin E2 receptors are differentially expressed in subpopulations of granulosa cells from primate periovulatory follicles. Biol Reprod 85:916-23
Duffy, Diane M (2011) Prostaglandin dehydrogenase (PGDH) in granulosa cells of primate periovulatory follicles is regulated by the ovulatory gonadotropin surge via multiple G proteins. Mol Cell Endocrinol 333:119-26

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