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: 2898899
• 负责人: Denis A Magoffin
• 金额: $ 30.67万
• 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/2898899
• 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，我们已经建立了这样的概念，即腔前卵泡的GC分泌的蛋白质扩散到生长卵泡附近的基质室中，这些蛋白质具有刺激内膜前细胞分化为内分泌细胞的能力，这些内分泌细胞表达LH受体并具有分泌雄激素的能力。这个过程不需要LH。我们进一步证实，已知IGF-1和SCF均由腔前卵泡中的GC分泌，IGF-1和SCF的组合可以刺激雄激素产生，而不依赖于LH，其方式与腔前卵泡分泌的物质非常相似。多囊卵巢综合征是最常见的生殖内分泌疾病，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。本研究的总体目标是明确IGF-I和SCF在卵泡膜分化和正常发育卵泡雄激素产生机制中的作用，并确定该机制是否参与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卵泡膜细胞的模型来表征相对重要性和IGF-1和SCF之间的相互作用，刺激卵泡膜LH受体，P450/SCC，3 β-HSD，P450/17 α mRNA和雄激素生物合成的表达。我们将研究IGF-1和SCF相互补充的分子机制，以诱导关键的类固醇生成和调节基因的表达，并激活卵泡膜细胞中的类固醇生成机制。我们将使用在SCF基因中具有各种特征性突变的小鼠品系来检查由突变引起的生殖缺陷的性质，以了解SCF在生殖功能和卵泡膜分化中的作用。最后，我们将测量大鼠、正常月经周期妇女和多囊卵巢综合征妇女不同发育阶段卵泡中IGF-I和SCF的表达模式，以确定SCF+IGF-I表达是否存在可能导致高雄激素血症和排卵功能障碍的改变。从这些研究中，我们将了解重要的信息，关于一种新的途径调节卵巢雄激素的生产不依赖于LH。希望这将为开发高雄激素血症的新治疗方法提供新的机会。