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.
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.
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.
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