REGULATION OF GENES BY T AND DHT IN RAT AND HUMAN PROSTA

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DESCRIPTION Although the principal androgen produced by the adult and fetal testis and circulating in the blood of males is T, many tissues such as the prostate gland, are dependent on the in situ conversion of T to DHT. Studies of patients deficient in one of the two isoenzymes that catalyze the conversion of T to DHT, as well as animal studies using specific inhibitors of 5a-reductase, have clearly demonstrated that T and DHT are not equivalent androgens, and that the formation of DHT is physiologically important for the differentiation and development of the ventral prostate gland and tissues of the male external genital tract. It is clear from studies of animals and humans with androgen resistance that both T and DHT bind to the same receptor protein within the nucleus of target cells. The objective of this project is to elucidate mechanisms by which two androgens account for the totality of androgen action during development. Two general hypotheses will be addressed in the proposed studies: 1) T and DHT elicit separate and unique androgenic responses during differentiation of the prostate gland, and 2) DHT formation is necessary to concentrate the androgenic signal in some tissues of the differentiating male urogenital tract. We do not feel that one hypothesis is mutually exclusive of the other, and in fact, have amassed preliminary data that support both. The proposed work is of enormous significance. Formation of DHT has been implicated in the pathogenesis of several human diseases, including BPH, acne, hirsutism, and male pattern baldness. The results of these studies will help define the distinct roles that T and DHT play in androgen physiology and indicate the directions that efforts to selectively interfere with the actions of T and DHT can take.