Insulin signaling in theca cells from polycystic ovaries

多囊卵巢卵泡膜细胞中的胰岛素信号传导

• 批准号: 6649704
• 负责人: Denis A Magoffin
• 金额: $ 22.45万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-08-21 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6649704
• 关键词: androgens; clinical research; female; glucose metabolism; glucose transport; graafian follicles; hormone regulation /control mechanism; human subject; insulin sensitivity /resistance; ovarian cysts; patient oriented research; polycystic ovary syndrome; steroid hormone biosynthesis; tissue /cell culture

DESCRIPTION (provided by applicant): Polycystic ovary syndrome (PCOS) is the most common reproductive endocrine disease in women of reproductive age. Approximately three-quarters of women with anovulatory infertility have PCOS, thus accounting for approximately one-third of women with secondary amenorrhea and approximately 90% of women with oligomenorrhea. Other consequences of PCOS are hirsutism, markedly increased incidence of recurrent early pregnancy loss, an estimated 11-fold increased risk of myocardial infarction between the ages of 50-61 years, and an increased risk of endometrial cancer at a young age. A consistent finding in women with PCOS is that the ovaries produce abnormally high amounts of androgens. There is good evidence to conclude that elevated androgens interfere with selection of dominant follicles and cause PCOS. Importantly, there is an association between insulin resistance and the androgen excess of PCOS. It is clear that insulin can stimulate ovarian androgen production, but a paradox exists: how can insulin hyperstimulate ovarian thecal androgen production in an insulin resistant woman? One of two hypotheses could explain the seeming paradox. Either the ovarian theca cells are not insulin resistant in insulin resistant women or there are distinct insulin signaling mechanisms regulating glucose metabolism and androgen production in theca cells. The purpose of the proposed studies is to determine if ovarian theca cells are insulin resistant in insulin resistant women, to explore the intracellular signaling mechanisms by which insulin regulates androgen biosynthesis, and to determine if there are differences in the concentrations and/or activities of key molecules mediating insulin action in theca cell from polycystic ovaries. To accomplish these goals, we will measure the sensitivity of skeletal muscle and ovarian theca cell glucose uptake in response to insulin to determine the relative sensitivity of these tissues to insulin in insulin sensitive and insulin resistant women with and without PCOS. We have established a human theca cell culture model in which we can examine the molecular details of insulin signaling. Importantly, increased androgen production and steroidogenic enzyme mRNA over-expression persist in the cultured cells in vitro. We propose to use this model to systematically determine the intracellular signaling pathway for insulin stimulation of CYP 17 activities and mRNA expression and then to compare the concentrations and activities of the signaling molecules between regularly cycling control women and women with PCOS. The results of these studies are expected to yield specific molecular targets for novel therapies to treat women with PCOS.

描述(申请人提供)：多囊卵巢综合征(PCOS)是育龄妇女最常见的生殖内分泌疾病。大约四分之三的无排卵性不孕症妇女患有多囊卵巢综合征，因此约占继发性闭经妇女的三分之一，约90%的月经稀少妇女。多囊卵巢综合征的其他后果包括多毛症、反复早孕丢失的发生率显著增加、50-61岁之间心肌梗死的风险估计增加11倍，以及年轻时子宫内膜癌的风险增加。在患有多囊卵巢综合征的女性中，一个一致的发现是卵巢产生了异常高水平的雄激素。有很好的证据表明，雄激素升高干扰了优势卵泡的选择，并导致PCOS。重要的是，胰岛素抵抗和PCOS的雄激素过剩之间存在关联。很明显，胰岛素可以刺激卵巢雄激素的产生，但存在一个悖论：在胰岛素抵抗的女性中，胰岛素如何过度刺激卵泡膜雄激素的产生？两种假设中的一种可以解释这一看似矛盾的现象。要么是胰岛素抵抗女性的卵巢膜细胞不存在胰岛素抵抗，要么是膜细胞中存在调节葡萄糖代谢和雄激素产生的独特的胰岛素信号机制。本研究的目的是确定胰岛素抵抗妇女的卵泡膜细胞是否存在胰岛素抵抗，探讨胰岛素调节雄激素生物合成的细胞内信号机制，以及多囊卵巢卵泡膜细胞中介导胰岛素作用的关键分子的浓度和/或活性是否存在差异。为了实现这些目标，我们将测量骨骼肌和卵巢膜细胞葡萄糖摄取对胰岛素的敏感性，以确定患有和不患有多囊卵巢综合征的胰岛素敏感和胰岛素抵抗女性这些组织对胰岛素的相对敏感性。我们已经建立了一个人卵泡膜细胞培养模型，在这个模型中，我们可以研究胰岛素信号的分子细节。重要的是，在体外培养的细胞中，雄激素的产生增加和类固醇合成酶mRNA的过度表达持续存在。我们建议使用这个模型来系统地确定胰岛素刺激细胞内CYP 17活性和mRNA表达的信号通路，然后比较正常周期对照组妇女和PCOS妇女的信号分子的浓度和活性。这些研究的结果有望为治疗多囊卵巢综合征的女性提供新的治疗方法的特定分子靶点。