The broad goal of this project is to investigate the critical autocrine/paracrine role of the inhibin/activin/follistatin system in normal human follicular development and in women with Polycystic Ovary Syndrome (PCOS). To address the underlying defects leading to the classic PCOS ovarian appearance of numerous peripherally arranged, small follicles, we hypothesize that an excess of bioavailable activin contributes to both increased follicular development as well as developmental arrest of maturing follicles. Our approach is to obtain transvaginal follicular aspirates from well-characterized normal or PCOS volunteers, which can then be used to document the progression from an activin-B dominant to an inhibin-A dominant microenvironment suggested by previous immunohistochemical approaches. Specifically, we propose:
Specific Aim 1 : To delineate the role of the intrafollicular inhibin/activin/follistatin axis in the autocrine/paracrine regulation of normal folliculogenesis and ovulation in the human.
Specific Aim 2. To characterize defects in inhibin/activin subunit biosynthesis, processing or dimerization in the abnormal follicular maturation observed in PCOS.
Specific Aim 3. To determine the role of intrafollicular follistatin in regulating activin activity, and thereby follicular growth, in women with PCOS.
Specific Aim 4. To determine the mechanism whereby FS regulates activin action at the cell surface in human granulosa cells and related cell line models. Thus, this Project strives to provide key information to facilitate the transition from bench (Specific Aim 4) to bedside (Specific Aims 2 and 3) while also providing a valuable normative database (Specific Aim 1) for analysis of PCOS and other studies of ovarian pathophysiology.
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