The goal of this research is to understand the mechanisms whereby luteinizing hormone (LH) either directly, or indirectly via locally synthesized steroids, regulates the structure-function of the peri-ovulatory follicle or corpus luteum (CL) in primates during the menstrual cycle. Recent evidence suggests that specific genomic progesterone receptor isoforms (PGR-A and -B) regulate different activities in target tissue;and the discovery of nongenomic PGR membrane components (PGRMC1 and 2) adds another dimension to possible P actions in the ovary. Likewise, the PI's evidence that LH and P regulate expression of one estrogen receptor isoform (ERss) reintroduces the concept of local E action in the primate CL. Finally, recent whole genome analyses of the dynamics of the transcriptome in the macaque ovary provide the basis for manipulative studies to unravel the cellular and molecular events, prominently in immune cell-mediated processes, that are LH-dependent and steroid (P or E)-dependent in the primate ovulatory follicle or CL. Therefore, further experiments are planned in the adult, female rhesus monkey during the natural menstrual cycle, to test the hypotheses that:
(Aim 1) genomic (PGR-A and -B) and nongenomic (PGRMC1 and 2) PR isoforms are differentially expressed and regulate different functions in the ovulatory, luteinizing follicle;
(Aim 2) LH/P-regulated estrogen receptor (E- ERss) expression and action is critical in controlling the functional lifespan of the CL;
and (Aim 3) LH/steroid (P and/or E)-regulated migration and action of luteal macrophages and neutrophils is essential for CL regression. In vivo protocols will "clamp" LH support, thereby ruling out steroid effects via the hypothalamic-pituitary axis: (1) during the periovulatory interval (controlled ovulation), or (2) during mid-to-late luteal phase (controlled luteal function). Protocols will be combined with intrafollicular administration of specific inhibitors (anti-sense RNAs) of PGR and PGRMC isoforms (Aim 1), steroid ablation with or without P or E replacement (Aims 2 and 3), and intra-luteal infusion of monocyte/neutrophil selective, chemokine-receptor (CCL2/MCP1-CCR2 and CCL3/MIP11 - CCR3) antagonists (Aim 3). Follicular/luteal morphology, genome-wide mRNAs and selected proteins, plus markers of luteal cell types and immune cell function will be analyzed with the assistance of the Affymetrix Gene Array and Immunology Resources Cores.

Public Health Relevance

These experiments will provide valuable information on the mechanisms controlling ovulation and the functional lifespan of the corpus luteum, and hence fertility, in primates. New insight will emerge on the interactions between the ovary and the immune system, particularly steroid regulation of macrophage/neutrophil migration and activity. Emerging concepts should refine clinical paradigms, e.g., the etiology and treatment of ovarian cysts, polycystic ovarian syndrome, luteal phase effects, and recurrent pregnancy loss.

Public Health Relevance

This application proposes research to understand how the major trophic hormone, luteinizing hormone (LH), either directly or indirectly via locally synthesized steroids (progesterone or estrogen), controls the structure- function of the ovulatory follicle and corpus luteum during the menstrual cycle.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD020869-27
Application #
8443878
Study Section
Cellular, Molecular and Integrative Reproduction Study Section (CMIR)
Program Officer
Taymans, Susan
Project Start
1985-07-01
Project End
2016-02-28
Budget Start
2013-03-01
Budget End
2014-02-28
Support Year
27
Fiscal Year
2013
Total Cost
$511,541
Indirect Cost
$219,232
Name
Oregon Health and Science University
Department
Obstetrics & Gynecology
Type
Other Domestic Higher Education
DUNS #
096997515
City
Portland
State
OR
Country
United States
Zip Code
97239
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
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
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
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
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
Hennebold, Jon D (2010) Preventing granulosa cell apoptosis through the action of a single microRNA. Biol Reprod 83:165-7
Peluffo, Marina C; Young, Kelly A; Hennebold, Jon D et al. (2009) Expression and regulation of tumor necrosis factor (TNF) and TNF-receptor family members in the macaque corpus luteum during the menstrual cycle. Mol Reprod Dev 76:367-78
Hernandez, Fatima; Peluffo, Marina C; Bas, Diana et al. (2009) Local effects of the sphingosine 1-phosphate on prostaglandin F2alpha-induced luteolysis in the pregnant rat. Mol Reprod Dev 76:1153-64
Bishop, Cecily V; Hennebold, Jon D; Stouffer, Richard L (2009) The effects of luteinizing hormone ablation/replacement versus steroid ablation/replacement on gene expression in the primate corpus luteum. Mol Hum Reprod 15:181-93

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