Pituitary PACAP gene regulation by hypothalamic, pituitary and gonadal factors

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DESCRIPTION (provided by applicant): Recent studies have demonstrated a clear role for pituitary adenylate cyclase-activating peptide (PACAP) in the regulation of gonadotropin biosynthesis and secretion. First defined as a hypothalamic-releasing factor, PACAP subsequently has been determined to have widespread distribution and function, including expression in the gonads, placenta, central and peripheral nervous systems, endocrine pancreas, and adrenal gland. Of particular relevance to this proposal, PACAP expression has been identified in pituitary gonadotrope cells, suggesting that PACAP may act as an autocrine-paracrine factor in this tissue. In view of its critical role in multiple physiologic systems, remarkably little is known regarding the regulation of PACAP gene expression. The primary objective of this proposal is to elucidate the hormonal factors, intracellular signaling systems, transcription factors, and cis-elements which regulate PACAP expression in the pituitary gonadotrope. In preliminary studies, we have observed the ability of gonadotropin-releasing hormone (GnRH) to stimulate PACAP gene expression and have initiated studies to identify GnRH-responsive DNA- regulatory regions in the PACAP gene promoter. The Specific Aims are: 1) To characterize the intracellular signaling pathways which mediate GnRH-activated PACAP gene expression, with a focus on putative AP-1 and CRE-like cis-elements, 2) To identify the transcription factor(s) which mediate GnRH-induced stimulation of PACAP gene promoter activity, 3) To define pituitary PACAP gene expression in primary rat pituitary cells under various physiologic states in vivo, and 4) To characterize the role of pulsatile GnRH, gonadal steroids and gonadal peptides as regulators of PACAP gene expression in vitro. Information obtained regarding the molecular and cellular regulation of PACAP expression is predicted to have broad relevance for the array of physiologic systems in which PACAP functions. More immediately, these studies will provide important insight into the fine-tuning of gonadotrope physiology, a requirement for normal reproductive function. In the longer term, it is predicted that these investigations will broaden our understanding, and ultimately improve treatment options, for the multiple disorders associated with abnormal gonadotropin expression, including delayed and precocious puberty, polycystic ovarian syndrome, and hypogonadotropic hypogonadism.