MOLECULAR MECHANISM FOR THE CONTROL OF AROMATASE IN MEN

控制男性芳香酶的分子机制

基本信息

批准号：
3153870
负责人：
GARY DAVID BERKOVITZ
金额：
$ 12.25万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1985
资助国家：
美国
起止时间：
1985-04-01 至 1989-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/3153870
关键词：
androgens cyclic AMP estrogens gynecomastia hormone metabolism hormone regulation /control mechanism human tissue male molecular pathology prostate disorder pseudohermaphroditism reproductive development scintillation spectrometry tissue /cell culture

项目摘要

The purpose of this project is to investigate the factors which regulate aromatase activity in order to better understand the physiology and pathology of male sexual development. The previously proposed role of estrogens in the pathogenesis of male pseudohermaphroditism, pubertal gynecomastia, benign prostatic hypertrophy, and male infertility underline the importance of studying the regulation of estrogen production. More than 80% of the circulating estrogens in normal men is derived from conversion of androgens by aromatase in extraglandular tissues. Although in vivo studies provide considerable information about the kinetics of aromatization, cell culture of tissues that are important sites of aromatization provides a unique opportunity for the study of factor which regulate the enzyme. Hence, other workers have focused on the aromatase in fibroblasts derived from adipose tissue. Recent studies in our laboratory demonstrted that the kinetics of aromatase in skin and adipose tissue fibroblasts were similar, suggesting that skin contributes to the total production of estrogens in men. Furthermore, our studies demonstrated that the regulation of aromatase in skin fibroblasts is somewhat different from from that previously described for adipose tissue cells. Therefore, the investigation of the regulation of aromatase in human skin fibroblasts grown in cell culture should provide new and valuable insights regarding the control of this enzyme. The purpose of this application will first be to define the factors which modulate baseline aromatase activity: site of skin biopsy, age of donor, plating density and passage number. Then, we will exlore the molecular mechanisms responsible for two patterns of regulation that we recently observed; the biphasic change in aromatase activity following glucocorticoid stimulation and the suppressive effects of androgens. In addition, we will compare the effects of cAMP and of steroid hormones on aromatase activity. Finally, we plan to investigate the factors responsible for the elevated levels of aromatase activity of skin fibroblasts derived from the members of an unusual kindred with familial gynecomastia due to elevated extra-glandular aromatase activity. Attempts will be made to determine the genetic transmission of this trait by studying clonal cell populations.

该项目的目的是调查调节的因素芳香化酶活性以更好地了解生理学和男性性发育的病理。先前提出的角色雄性假磷灰石的发病机理中的雌激素，青春期妇科，良性前列腺肥大和男性不育下划线研究雌激素产生调节的重要性。更多的正常男性中的循环雌激素的80％来自通过芳香化酶在邻域组织中的芳香酶转化。虽然体内研究提供了有关动力学的大量信息芳香化，组织的细胞培养芳香化为研究因素提供了独特的机会调节酶。因此，其他工人专注于芳香酶源自脂肪组织的成纤维细胞。我们实验室的最新研究证明皮肤和脂肪组织中芳香酶的动力学成纤维细胞相似，表明皮肤有助于总男性雌激素的产生。此外，我们的研究表明皮肤成纤维细胞中芳香酶的调节与从先前描述的是脂肪组织细胞。因此，研究人皮肤成纤维细胞中芳香酶的调节在细胞培养中生长的应提供有关有关的新的和有价值的见解该酶的控制。该应用程序的目的首先是定义因素调节基线芳香化酶活性：皮肤活检部位，供体的年龄，电镀密度和通过数。然后，我们将超越分子造成我们最近的两种调节模式的机制观察到；以下芳香化酶活性的双相变化糖皮质激素刺激和雄激素的抑制作用。在此外，我们将比较营地和类固醇激素对芳香酶活性。最后，我们计划调查因素负责皮肤的芳香化酶活性升高源自与家族的不寻常亲属的成员衍生的成纤维细胞妇科乳腺癌是由于gy虫外芳香酶活性升高而引起的。尝试将通过研究克隆细胞群。