GROWTH FACTOR CONTROL OF OVARIAN ANDROGEN BIOSYNTHESIS

卵巢雄激素生物合成的生长因子控制

• 批准号: 6181805
• 负责人: Denis A Magoffin
• 金额: $ 29.21万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-06-01 至 2002-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6181805
• 关键词: androgens; cell differentiation; cyclic AMP; developmental genetics; female; gene expression; gene mutation; graafian follicles; granulosa cell; growth factor; hormone receptor; hormone regulation /control mechanism; human subject; hydroxysteroid dehydrogenases; insulinlike growth factor; laboratory mouse; laboratory rat; luteinizing hormone; oogenesis; pituitary gonadal axis; polycystic ovary syndrome; receptor coupling; secretion; steroid hormone biosynthesis; women's health

In preliminary studies we have established the concept that the GC of pre-antral follicles secrete proteins that diffuse into the stromal compartment adjacent to the growing follicles that have the capability of stimulating the differentiation of pre-theca cells into endocrine cells in the theca interna that express LH receptors and have the capacity to secrete androgens. This process occurs without the need for LH. We have further established that the combination of IGF-1 and SCF, both of which are known to be secreted by GC in pre-antral follicles, can stimulate androgen production independent of LH in a manner very similar to the substances secreted by pre-antral follicles. The most common reproductive endocrine disorder, polycystic ovary syndrome, is characterized by excessive androgen production by the ovarian theca cells but the mechanism stimulating thecal androgen production is incompletely understood. The overall goals of this proposal are to define the roles of IGF-I and SCF in the mechanism of theca differentiation and androgen production in normally developing follicles and to determine whether this mechanism could be involved in the pathogenesis of PCOS. To accomplish these goals we will use our unique model of differentiating ovarian thecal cells to characterize the relative importance and the interactions between IGF-I and SCF with respect to stimulating thecal expression of LH receptor, P450/SCC, 3beta-HSD, P450/17alpha mRNAs and androgen biosynthesis. We will examine the molecular mechanisms by which IGF-1 and SCF complement each other to induce the expression of the key steroidogenic and regulatory genes and activate the steroidogenic machinery in theca cells. We will use strains of mice that have various well-characterized mutation in the SCF gene to examine the nature of reproductive defects caused by the mutations in an effort to understand the role of SCF in reproductive function and thecal differentiation. Finally, we will measure the expression patterns of IGF-I and SCF in follicles at different stages of development in both rats and women with normal menstrual cycles and women with polycystic ovary syndrome to determine if there are alterations in SCF+IGF-I expression that could contribute to hyperandrogenism and ovulatory dysfunction. From these studies we will learn important information regarding a novel pathway regulating ovarian androgen production independent of LH. It is hoped that this will provide novel opportunities for developing new treatments for hyperandrogenism.

在初步研究中，我们建立了这样的概念，即窦前卵泡的GC分泌的蛋白质扩散到邻近生长卵泡的基质室中，这些蛋白质能够刺激卵泡膜前细胞分化为内卵泡膜中的内分泌细胞，表达LH受体并具有分泌雄激素的能力。这个过程的发生不需要 LH。我们进一步确定IGF-1和SCF的组合（已知这两种物质均由窦前卵泡中的GC分泌）可以以与窦前卵泡分泌的物质非常相似的方式刺激独立于LH的雄激素产生。最常见的生殖内分泌疾病是多囊卵巢综合征，其特征是卵巢卵泡膜细胞产生过多的雄激素，但刺激卵泡膜雄激素产生的机制尚不完全清楚。该提案的总体目标是明确 IGF-I 和 SCF 在正常发育的卵泡中卵泡膜分化​​和雄激素产生机制中的作用，并确定该机制是否可能参与 PCOS 的发病机制。为了实现这些目标，我们将使用我们独特的分化卵巢膜细胞模型来表征 IGF-I 和 SCF 之间在刺激 LH 受体、P450/SCC、3beta-HSD、P450/17α mRNA 和雄激素生物合成的膜表达方面的相对重要性和相互作用。我们将研究 IGF-1 和 SCF 相互补充以诱导关键类固醇生成和调节基因表达并激活卵泡膜细胞中类固醇生成机制的分子机制。我们将使用 SCF 基因中具有各种明确特征突变的小鼠品系来检查突变引起的生殖缺陷的性质，以了解 SCF 在生殖功能和鞘膜分化中的作用。最后，我们将测量正常月经周期的大鼠和女性以及患有多囊卵巢综合征的女性的卵泡中不同发育阶段的 IGF-I 和 SCF 的表达模式，以确定 SCF+IGF-I 表达的变化是否可能导致雄激素过多症和排卵功能障碍。从这些研究中，我们将了解有关独立于 LH 调节卵巢雄激素产生的新途径的重要信息。希望这将为开发高雄激素血症的新疗法提供新的机会。