MECHANISMS OF INSULIN/LH SYNERGY IN THECAL CELLS

膜细胞中胰岛素/LH 协同作用的机制

• 批准号: 6590768
• 负责人: JOHANNES D VELDHUIS
• 金额: $ 17.42万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-01 至 2003-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6590768
• 关键词: androgens; female; graafian follicles; hormone biosynthesis; hormone regulation /control mechanism; human subject; hyperinsulinism; insulin; insulin sensitivity /resistance; luteinizing hormone; nucleic acid sequence; polycystic ovary syndrome; swine; transfection

The polycystic ovarian syndrome (PCOS) represents the most common reproductive pathophysiology in pre-menopausal women. Hallmarks of PCOS are increased LH secretion, altered insulin action, and augment ovarian androgen biosynthesis. Overall working hypothesis is that LH and insulin synergize at the level of the ovarian theca cell to drive excessive androgen secretion. Although LH and insulin ( or IGF-1) can synergistically amplify ovarian androgen biosynthesis in vivo and by human, hen, rat and pig theca cells in vitro (present data), how LH and insulin collaborate in this fashion is not known. This project will investigate the clinical and molecular mechanisms of lH and insulin synergy in PCOS patients in vivo and on (pig) theca cells in vitro. Our individual aims arise from the following specific hypotheses: I. Preferential suppression of hyperinsulinism (via metformin treatment) of LH hypersecretion (via leuprolide down-regulation) alters the testosterone secretory response to human recombinant LH infusions in PCOS patients; II. In vitro, in pig theca-cell populations, LH and insulin synergistically up-regulate the molecular expression of critical genes that control sterol commitment to androgen biosynthesis; namely, the low- density lipoprotein (LDL) receptor, the steroidogenic acute responsive protein (StAR), and the 17-alpha hydroxylase enzyme; III. In situ, at the single-theca-cell level, LH and insulin synergize by coordinately enhancing multiple sterol-regulatory gene co-expression in individual theca cells; and IV. There are pivotal cis-DNA promoter elements in the StAR and LDL receptor genes that mediate responses to the intracellular signals generated by insulin and LH, acting singly and synergistically. The preceding clinical and basic-science hypotheses and corresponding experiments should help identify novel clinical and molecular mechanisms that govern theca-cell androgen biosynthesis, and thereby offer new insights into the basic pathobiology of PCOS.

多囊卵巢综合征(PCOS)是最常见的 绝经前妇女的生殖病理生理学。多囊卵巢综合征的特征 促黄体生成素分泌增加，胰岛素作用改变，卵巢增大 雄激素的生物合成。总体工作假设是促黄体生成素和胰岛素 在卵泡膜细胞水平上协同作用，以驱动过度 雄激素分泌。虽然黄体生成素和胰岛素(或IGF-1)可以 协同放大体内和体外的卵巢雄激素生物合成 人、鸡、大鼠和猪卵泡膜细胞的体外培养(目前的数据)，黄体生成素和 以这种方式合作的胰岛素尚不为人所知。这个项目将 探讨促黄体生成素和胰岛素的临床及分子机制 多囊卵巢综合征患者体内和体外对(猪)膜细胞的协同作用。我们的 个人目标源于以下具体假设： 优先抑制高胰岛素血症(通过二甲双胍治疗) 促黄体生成素高分泌(通过亮丙瑞林下调)改变 多囊卵巢综合征患者输注重组人促黄体生成素对睾酮分泌的影响 患者； II.在体外，在猪卵泡膜细胞群体中，促黄体生成素和胰岛素 协同上调关键基因的分子表达 控制类固醇对雄激素生物合成的承诺；即，低... 密度脂蛋白(LDL)受体，激素性急性反应 蛋白质(STAR)和17-α羟基酶； 在单膜细胞水平上，在原位，促黄体生成素和胰岛素通过 协同增强多个甾醇调节基因的共表达 单个膜细胞；以及 四、STAR和LDL中含有关键的顺式DNA启动子元件 调节细胞内信号反应的受体基因 由胰岛素和黄体生成素产生，单独作用，协同作用。 前人的临床和基础科学假说及相应的 实验应该有助于确定新的临床和分子机制 管理膜细胞雄激素的生物合成，从而提供新的 对多囊卵巢综合征的基本病理生物学的洞察。