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.
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