MOLECULAR MECHANISM FOR THE CONTROL OF AROMATASE IN MEN

这个项目的目的是调查调节的因素 为了更好地了解芳香酶的活性和生理学 男性性发育的病理学。先前提议的角色是 雌激素在青春期男性假两性畸形发病机制中的作用 女性乳房发育症、良性前列腺肥大和男性不育 研究雌激素生成调控的重要性。更多 正常男性体内80%以上的循环雌激素来自 腺外组织中芳香化酶对雄激素的转化。虽然 体内研究提供了大量关于药物动力学的信息。 芳构化，是组织的重要部位的细胞培养 芳构化为研究影响芳构化的因素提供了难得的机会 调节这种酶。因此，其他工人将注意力集中在芳香酶上。 成纤维细胞来源于脂肪组织。我们实验室的最新研究 表明皮肤和脂肪组织中芳香化酶的动力学 成纤维细胞相似，这表明皮肤在总数中所占的比例 男性体内雌激素的产生。此外，我们的研究表明， 芳香酶在皮肤成纤维细胞中的调节与 与之前描述的脂肪组织细胞的情况不同。因此， 芳香化酶在人皮肤成纤维细胞中的调控研究 在细胞培养中生长应该提供关于 对这种酶的控制。 本申请的目的首先是定义以下因素 调节基础芳香酶活性：皮肤活检部位，供者年龄， 电镀密度和通道数。然后，我们将发掘分子 负责我们最近的两种监管模式的机制 观察到芳香酶活性的双相变化。 糖皮质激素的刺激和雄激素的抑制作用。在……里面 此外，我们将比较cAMP和类固醇激素对 芳香酶活性。最后，我们计划调查这些因素 导致皮肤芳香酶活性升高的原因 成纤维细胞来源于一个不寻常的家族成员 由于腺外芳香酶活性升高而导致的女性乳房发育症。尝试 将通过以下方式来确定这一特征的遗传传递 研究克隆细胞群体。

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.