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

描述 虽然成人和胎儿睾丸产生的主要雄激素和 在男性血液中循环的是T，许多组织，如前列腺 腺，是依赖于原位转换的T到DHT。 研究 缺乏催化转化的两种同工酶之一的患者 的T到DHT，以及使用特异性抑制剂的动物研究， 5 α-还原酶，已经清楚地证明了T和DHT是不等价的， 雄激素，而双氢睾酮的形成是生理上重要的， 腹侧前列腺的分化和发育， 男性外生殖道的组织。 研究表明， 雄激素抵抗的动物和人类，T和DHT都结合到 靶细胞核内的相同受体蛋白。 的目标 该项目旨在阐明两种雄激素导致 发育过程中雄激素作用的总和。 两个一般假设 将在拟议的研究中得到解决：1）T和DHT引起单独的， 前列腺分化过程中独特的雄激素反应， 和2）DHT的形成是必要的，以集中雄激素信号， 分化中的男性泌尿生殖道的某些组织。 我们不觉得 一个假设与另一个假设相互排斥，事实上， 收集的初步数据支持这两种观点。 拟议的工作是 巨大的意义 双氢睾酮的形成与 几种人类疾病的发病机制，包括BPH，痤疮，多毛症， 男性型脱发 这些研究的结果将有助于定义 T和DHT在雄激素生理学中发挥不同的作用，并表明 努力选择性地干扰T的行为， DHT可以。

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.