ACTION OF HORMONES ON PROTEIN AND RNA METABOLISM

为了深入了解雄激素作用的正常途径， 胚胎期和胚后期的生命， 雄激素作用的损伤可能导致疾病，实验将 针对雄激素作用的三个主要阶段中的每一个- 雄激素与受体的结合，睾酮的5 α-还原， 二氢睾酮和雄激素芳构化为雌激素。 在 关于雄激素受体，我们将分析其分子缺陷， 选择具有损害受体功能的突变的患者， 用于诊断和追踪疾病的改进的功能和遗传技术 雄激素受体突变的遗传，定义对照 调节雄激素受体基因表达的元件，和 研究不同年龄组雄激素受体水平的调节 雄激素靶组织。 为了深入了解 在雄激素生理学的双氢睾酮的形成，我们将调查 双氢睾酮形成放大 雄激素信号在体内和体外系统中。 定义的角色 雄激素作用中的雌激素代谢产物，我们分析了 正常卵巢和正常卵巢中芳香化酶起始位点的性质 腺外雌激素形成的组织（脑），并研究 组织特异性基因表达的调控机制 睾丸细胞系，其中芳香化酶的控制被打乱。 在 总之，我们将利用生理、遗传、内分泌和 雄激素作用的分子分析技术及其应用 病理生理学 这些研究与人类疾病直接相关- 这两种疾病都是常见的先天缺陷，如尿道下裂和 男性不常见疾病的性别分化 由于雄激素抵抗导致的假两性畸形。

To provide insight into the normal pathway of androgen action during embryonic and, postembryonic life and into the mechanism by which impairments of androgen action can result in disease, experiments will be addressed to each of the three principal phases of androgen action - binding of androgen to the receptor, 5alpha-reduction of testosterone to dihydrotestosterone, and aromatization of androgen to estrogen. In regard to the androgen receptor, we will analyze the molecular defects in selected patients with mutations that impair receptor function, develop improved functional and genetic techniques for diagnosing and tracing the Inheritance of mutations of the androgen receptor, define the control elements that regulate expression of the androgen receptor gene, and Investigate the regulation of androgen receptor levels in different androgen target tissues. To provide insight into the role of dihydrotestosterone formation in androgen physiology, we will Investigate the mechanism by which dihydrotestosterone formation amplifies the androgen signal In vivo and in in vitro systems. To define the role of the estrogenic metabolites of androgen in androgen action, we analyze the nature of the start sites for aromatase in normal ovary and a normal tissue in which extraglandular estrogen is formed (brain) and study the mechanism of the control of tissue-specific gene expression in a testicular cell line in which the control of aromatase is derranged. In summary, we will utilize physiological, genetic, endocrinological, and molecular techniques for analysis of androgen action and its pathophysiology. These studies have direct relevance to human disease - both for common birth defects such as hypospadias and for impairment of sexual differentiation in the less common disorders of male pseudohermaphroditism due to androgen resistance.