GONADOTROPIN-RELEASING HORMONE ACTION

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 自从20世纪70年代初分离出促性腺激素释放激素(GnRH)以来，基础和临床发现为GnRH类似物提供了用途。这些治疗包括治疗子宫内膜异位症/子宫肌瘤、多囊卵巢疾病、围绝经期、保护卵巢和睾丸(即在化疗期间)、辅助生殖、性早熟、男性和女性节育、前列腺癌、卵巢癌和乳腺癌、隐睾症和其他疾病。对促性腺激素释放激素作用的研究为神经内分泌肽领域提供了大量有用的基础信息。此外，目前在科学和专利文献中描述了近10,000个具有生物活性的促性腺激素释放激素类似物，为了解结构-活性关系提供了一个精致的数据库；这些类似物包括定义明确的全激动剂和全拮抗剂，其中许多是代谢稳定的或具有其他理想的特征。对这种荷尔蒙作用机制的更好理解可能会带来改进药物(即副作用更少、口服活性更低、更便宜)和更具体的治疗方法的机会。“非传统”办法也有潜力；本提案描述了涉及其中一些办法。这项研究的具体目标将促进我们的基本理解，并将确定潜在的治疗干预的新地点和方法。这些研究包括：1.GnRH受体-受体相互作用的化学计量学和作用；2.GnRH受体与效应器和其他调节蛋白的偶联；3.实时动态检测GnRH刺激的启动子表达；4.基于部分激活性的治疗方法；5.灵长类动物模型中的生理终点。

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.