OVARIAN CATECHOLESTROGENS

卵巢儿茶酚雌激素

• 批准号: 3325983
• 负责人: JAMES M HAMMOND
• 金额: $ 14.85万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 1989
• 资助国家: 美国
• 起止时间: 1989-12-01 至 1994-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3325983
• 关键词: antihypercholesterolemic agent; catecholamines; catechols; cell differentiation; complementary DNA; estrogen analog; gonadotropin releasing factor; graafian follicles; granulosa cell; hormone metabolism; hormone regulation /control mechanism; hypothalamic pituitary axis; infant animal; methylation; progesterone; steroid biosynthesis; steroid hormone; swine; tissue /cell culture

This proposal addresses autocrine/paracrine actions of catecholestrogens in the porcine ovarian follicle. Our data have shown that these novel compounds have substantial potential as local ovarian regulators since they are synthesized in the ovarian follicle and act to promote differentiation of ovarian follicular cells. In the projected period of support, we will aim at a more detailed and integrated understanding of this putative regulatory system at each of several points which may determine their impact. The biosynthesis of catecholestrogens will be further studied by understanding the nature and regulation of the key biosynthetic enzyme -- estrogen-2-hydroxylase (E-2-H). To approach this issue, the hormonal regulation of this enzyme will be studied in cultured granulosa and theca cells and in follicular tissue from gonadotropin-treated swing. Levels of the catecholestrogens themselves will also be determined in follicular flui and culture medium. The nature of the ovarian E-2-H and its mRNA will be studied with antibodies and cDNA probes. Once validated, such reagents wil lead to detailed studies of enzyme biosynthesis and its regulation. Next, we will study the significance of the metabolism of catecholestrogens in th ovary, since degradation of these steroids is important to their levels and action. For these studies, we will examine CE metabolism via catechol-O- methyltransferase (COMT), its location and hormonal control. Further, we will determine the mechanism of action of 2-O-methyl-estradiol, the chief product of COMT. Finally, we will determine the cellular locus and mechanism of action of the catecholestrogens on ovarian granulosa cells. In these studies, we will evaluate the effects of catecholestrogens on the activity and biosynthesis of the enzymes of the progestin biosynthetic pathway. In particular, effects of catecholestrogens on cyclic AMP generation, and in regulation of HMG-CoA-reductase and cholesterol side- chain cleavage will be determined. These studies are expected to establish a unique role for these compounds in the development of the preovulatory follicle.

该提案涉及在 猪卵巢卵泡。 我们的数据表明这些小说 作为当地卵巢调节器，化合物具有巨大的潜力 在卵巢卵泡中合成并作用以促进分化 卵巢卵泡细胞。 在预计的支持时期，我们将 致力于对此推定的更详细和综合的理解 几个点的调节系统可能决定他们 影响。 Catecholestrogens的生物合成将通过 了解关键生物合成酶的性质和调节 - 雌激素-2-羟化酶（E-2-H）。 为了解决这个问题，荷尔蒙 该酶的调节将在培养的颗粒和theca中进行研究 细胞和促促性腺激素处理的秋千的卵泡组织。 水平 Catecholestrogen本身也将在卵泡中确定 和培养基。 卵巢E-2-H及其mRNA的性质将是 用抗体和cDNA探针进行了研究。 一旦得到验证，此类试剂将 导致对酶生物合成及其调节的详细研究。 下一个， 我们将研究Catecholestrogen代谢在TH中的重要性 卵巢，因为这些类固醇的降解对它们的水平很重要，并且 行动。 对于这些研究，我们将通过Catechol-O-检查CE代谢 甲基转移酶（COMT），其位置和激素对照。 此外，我们 将确定2-O-甲基雌二醇的作用机理， COMT的产品。 最后，我们将确定细胞基因座和 cate雌激素对卵巢颗粒细胞的作用机理。 在这些研究中，我们将评估Catecholestrogen对 孕激素生物合成酶的活性和生物合成 路径。 特别是，catecholestrogen对环状AMP的影响 在HMG-COA-还原酶和胆固醇侧的调节中产生 将确定链裂解。 这些研究有望建立 这些化合物在卵巢预制的开发中的独特作用 卵泡。