The proposed research is designed to test the hypothesis that modulation of gonadotropin receptors, their intracellular messenger systems (e.g., adenylate cyclase) or the coupling of these membrane components is an important mechanism regulating the primate corpus luteum during the menstrual cycle and early pregnancy. Based on progress in this laboratory, the metabolism of arachidonic acid in the corpus luteum will be modified: (1) to identify products (e.g., prostaglandins) , which have local luteotropic or luteolytic actions during the menstrual cycle, and (2) to examine the effects of these paracrine factors on the gonadotropin receptor-adenylate cyclase system in luteal tissue. Studies are also planned in a novel model of early pregnancy: (3) to investigate the mechanisms resulting in homologous desensitization of adenylate cyclase in the primate corpus luteum during CG exposure, and (4) to define the relationship between changes in the gonadotropin receptor-adenylate cyclase system and the steroidogenic and peptidergic funtions of the corpus luteum. The adult, female rhesus monkey continues as the animal of choice for this project. Arachidonate metabolism will be modulated and monitored by drug infusions directly into the corpus luteum and blood collection from the utero-ovarian vein (and aorta), respectively. Levels of progesterone, LH and prostaglandins in the blood will be measured by radioimmunoassay. A regimen of human CG which invokes pregnancy-like patterns of circulating gonadotropin will be employed to simulate the rescue of the corpus luteum in early pregnancy. Adenylate cyclase activity will be assessed by the conversion of (alpha 32P)ATP to (32P) cyclic AMP. Available and occupied receptors will be characterized via specific 125I-hCG binding and radioimmunoassay of eluted CG, respectively. Crosslinked (125I)hCG-receptors will be solubilized and subjected to column chromatography and SDS-gel electrophoresis. Luteal cells from simulated early pregnancy will be incubated in vitro to discern their response to gonadotropins, prostaglandins and analogs of intracellular messengers (e.g., dibutryl cyclic AMP, a Ca+2 ionophore A23178 and oleoylacetylglycerol). These studies will (a) broaden our understanding of the gonadotropin receptor-second messenger systems in primate species, and (b) help elucidate the endocrine and paracrine processes regulating luteal function during the menstrual cycle and early pregnancy, with direct application to controlling fertility and infertility in women.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
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Biochemical Endocrinology Study Section (BCE)
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Oregon Regional Primate Research Center
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Bishop, Cecily V; Xu, Fuhua; Steinbach, Rosemary et al. (2017) Changes in immune cell distribution and their cytokine/chemokine production during regression of the rhesus macaque corpus luteum. Biol Reprod 96:1210-1220
Bishop, Cecily V; Hennebold, Jon D; Kahl, Christoph A et al. (2016) Knockdown of Progesterone Receptor (PGR) in Macaque Granulosa Cells Disrupts Ovulation and Progesterone Production. Biol Reprod 94:109
Bishop, Cecily V; Xu, Fuhua; Molskness, Theodore A et al. (2015) Dynamics of Immune Cell Types Within the Macaque Corpus Luteum During the Menstrual Cycle: Role of Progesterone. Biol Reprod 93:112
Bishop, Cecily V; Molskness, Theodore A; Xu, Fuhua et al. (2014) Quantification of dynamic changes to blood volume and vascular flow in the primate corpus luteum during the menstrual cycle. J Med Primatol 43:445-54
Bishop, C V; Aazzerah, R A; Quennoz, L M et al. (2014) Effects of steroid ablation and progestin replacement on the transcriptome of the primate corpus luteum during simulated early pregnancy. Mol Hum Reprod 20:222-34
Stouffer, Richard L; Bishop, Cecily V; Bogan, Randy L et al. (2013) Endocrine and local control of the primate corpus luteum. Reprod Biol 13:259-71
Bishop, C V; Satterwhite, S; Xu, L et al. (2012) Microarray analysis of the primate luteal transcriptome during chorionic gonadotrophin administration simulating early pregnancy. Mol Hum Reprod 18:216-27
Adam, M; Saller, S; Ströbl, S et al. (2012) Decorin is a part of the ovarian extracellular matrix in primates and may act as a signaling molecule. Hum Reprod 27:3249-58
Bishop, C V; Bogan, R L; Hennebold, J D et al. (2011) Analysis of microarray data from the macaque corpus luteum; the search for common themes in primate luteal regression. Mol Hum Reprod 17:143-51
Xu, Fuhua; Stouffer, Richard L; Muller, Jorg et al. (2011) Dynamics of the transcriptome in the primate ovulatory follicle. Mol Hum Reprod 17:152-65

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