GONADOTROPIN-RELEASING HORMONE ACTION

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Since isolation of gonadotropin-releasing hormone (GnRH) in the early 1970s, basic and clinical discoveries have presented uses for GnRH analogs. Among these are treatments for endometriosis/fibroids, polycystic ovary disease, perimenopause, protection of the ovary and testes (i.e., during chemotherapy), assisted reproduction, precocious puberty, male and female birth control, prostatic, ovarian and mammary carcinomas, cryptorchidism, and other conditions. Studies of GnRH action have provided a great deal of useful, basic information to the field of neuroendocrine peptides. In addition, nearly 10,000 biologically active GnRH analogs are now described in the scientific and patent literature, providing an exquisite database for understanding structure-activity relations; these analogs include well-defined full agonists and full antagonists, many of which are metabolically stable or have other desirable characteristics. Improved understanding of the mechanism of action of this hormone will likely lead to opportunities for improved drugs (i.e., fewer side effects, orally active and cheaper) and more specific therapies. "Non-traditional" approaches also have potential; approaches involving some of these are described in the present proposal. The specific aims of this study will advance both our basic understanding and will identify new sites and approaches potentially amenable to therapeutic intervention. These include: I. Stoichiometry and role of GnRH receptor-receptor interactions; II. GnRH receptor coupling to effectors and other regulatory proteins; III. Real-time dynamic examination of GnRH-stimulated promoter expression; IV. Therapeutic approaches based on partial agonism; V. Physiological endpoints in a primate model.