ROLE OF A GONADAL FSH BINDING COMPETITOR IN FSH ACTION

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The long term goal of this research is to test the hypothesis that FSH receptor binding competitors (FRBC) can regulate the biological action of FSH, and are therefore essential components in the control of normal developmental, physiologic, and patholophysiologic functions of the gonad. The immediate focus of the studies proposed here is to purify and characterize a 58,000 MW FRBC that was first identified in follicular fluid by its binding to FSH receptors and antisera, and by its biological action as an FSH agonist in vitro. Furthermore, FRBC is antigenically and biochemically related to the precursor protein (58,00 MW) of the alpha inhibin subunit, also of gonadal origin, suggesting the possibility that regulation of FRBC posttranslational processing can modulate FSH biological action at the gonadal FSH receptor in a novel way. Specific Aim 1 involves further purification and characterization of FRBC, confirmation of bioactivity, and microsequencing to affirm the relationship of FRBC to alpha inhibin precursor. Specific monoclonal antibodies to different regions of FRBC will be raised to improve purification, and permit immunochemical detection of FRBC or its fragments in subsequent aims. Specific Aim 2 will explore the anatomical distribution of FRBC, as well as the hormonal regulation of synthesis, processing and secretion of FRBC using primary cultures of gonadal cells responsible for producing and secreting FRBC. Specific Aim 3 uses antibodies and FRBC from Aim 1 that are characterized in Aim 2 to develop specific assays for FRBC in serum and follicular fluid in patients with FSH-related reproductive disorders. Results from these studies should 1) confirm the existence of a local FSH regulatory system, 2) provide probes for studying the biochemistry and physiological role of FRBC, 3) elucidate regulatory mechanisms for posttranslational processing of FRBC, 4) explore the exciting interrelationship between FRBC, and FSH agonist, and alpha inhibin, which is responsible for suppressing FSH levels, and 5) evaluate the role of FRBC in human reproductive physiology, especially in control of gametogenesis and a potential role of FRBCs in disease states such as premature ovarian failure.