MOLECULAR MECHANISM FOR THE CONTROL OF AROMATASE IN MEN

控制男性芳香酶的分子机制

• 批准号: 3233645
• 负责人: GARY DAVID BERKOVITZ
• 金额: $ 14.39万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 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/3233645
• 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

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.

本项目的目的是调查调节 芳香酶活性，以便更好地了解生理学和 男性性发育的病理学。 先前提出的作用 雌激素在男性假两性畸形发病机制中的作用 男性乳房发育、良性前列腺肥大和男性不育 研究雌激素产生调节的重要性。 更 正常男性体内80%以上的循环雌激素来自 腺外组织中雄激素通过芳香化酶的转化。 虽然 体内研究提供了大量关于 芳构化，细胞培养的组织，是重要的网站， 芳构化为研究影响芳构化的因素提供了独特的机会， 调节酶。 因此，其他工作者将注意力集中在芳香化酶上， 来源于脂肪组织的成纤维细胞。 我们实验室最近的研究 证明了皮肤和脂肪组织中芳香化酶的动力学 成纤维细胞是相似的，这表明皮肤有助于总的 男性体内雌激素的产生。 此外，我们的研究表明， 皮肤成纤维细胞中芳香化酶调节与 与先前描述的脂肪组织细胞不同。 因此 人皮肤成纤维细胞芳香化酶调控的研究 在细胞培养中生长应该提供新的和有价值的见解， 控制这种酶。 本申请的目的首先是定义 调节基线芳香酶活性：皮肤活检部位，供体年龄， 平板接种密度和传代次数。 然后，我们将探索分子 负责两种调控模式的机制， 观察到;芳香酶活性的双相变化， 糖皮质激素刺激和雄激素的抑制作用。 在 此外，我们将比较cAMP和类固醇激素对 芳香化酶活性 最后，我们计划调查这些因素 负责皮肤芳香化酶活性水平的升高 成纤维细胞来源于一个不寻常的家族成员， 由于腺体外芳香化酶活性升高而引起的男性乳房发育。 尝试 将通过以下方式确定这种特征的遗传传递： 研究克隆细胞群。