Role of Androgen Excess in Provoking Oxidative Stress in Females

雄激素过量在引发女性氧化应激中的作用

• 批准号: 7706895
• 负责人: FRANK MAUVIS-JARVIS
• 金额: $ 23.49万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7706895
• 关键词: Adipocytes; Age; Androgens; Apoptosis; Biology; Catabolism; Cells; Chronic; Collaborations; Data; Diabetes Mellitus; Endocrine System Diseases; Fatty acid glycerol esters; Female; Gene Expression; Goals; Gonadal Steroid Hormones; Hyperandrogenism; Inflammation; Insulin; Insulin Resistance; Investigation; Islets of Langerhans; Knockout Mice; Knowledge; Metabolic syndrome; Mitochondria; Mus; Non-Insulin-Dependent Diabetes Mellitus; Oxidative Stress; Pancreas; Polycystic Ovary Syndrome; Predisposition; Production; Qualifying; Reactive Oxygen Species; Reagent; Research; Role; Serum; Support of Research; Testing; Testosterone; Woman; Women' s Health; adiponectin; base; cytokine; design; experience; improved; innovation; insulin secretion; prevent; programs; reproductive; sex

The polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women of reproductive age in the U.S. The PCOS present with hyperandrogenism accompanied by chronic inflammation, insulin resistance and type 2 diabetes (T2DM). Evidence presented in this proposal suggests that in women and mice, excess testosterone production generates inflammation which alters fat biology and insulin production, thus contributing to insulin resistance, the metabolic syndrome and T2DM. Despite these observations, the evidence that testosterone directly alters insulin secretion from pancreatic ¿-cells is lacking and the role of testosterone in disrupting fat biology, thus provoking insulin resistance, has not been investigated. The goal of this application is to demonstrate that excess testosterone in females predisposes to the metabolic syndrome and T2DM by acting on AR and provoking oxidative stress in pancreatic ¿-cells and in fat-cells. The specific aims of this application are: To demonstrate, through use of the ¿-cell AR knockout mouse (¿ARKO) that in females, excess testosterone activation of AR in ¿-cells provokes insulin-deficient diabetes. We will test the hypothesis that excess testosterone activation of AR in ¿-cells provokes oxidative stress. We will use a fat-cell AR knockout mouse (FARKO) to establish that, in females, excess testosterone activation of AR in adipocytes alters adipocytokines secretion and provokes systemic inflammation and insulin resistance. Finally, we will test the hypothesis using FARKO female mice and adipocytes that excess testosterone action on AR in adipocytes provokes oxidative stress and disrupts adipocytokines production. Successful completion of these studies will help define the AR as a target in hyperandrogenic women. This will help this center program in achieving its goal of supporting research to improve women's health.

多囊卵巢综合征(PCOS)是育龄妇女最常见的内分泌疾病 美国的年龄：多囊卵巢综合征患者伴有高雄激素血症伴慢性炎症、胰岛素 耐药性与2型糖尿病(T2 DM)这项提案中提出的证据表明，在女性和 在老鼠身上，过量的睾丸素产生炎症，从而改变脂肪生物和胰岛素的产生， 从而导致胰岛素抵抗、代谢综合征和T2 DM。尽管有这些观察，但 缺乏睾丸激素直接改变胰腺细胞胰岛素分泌的证据，而睾丸激素的作用 睾酮在扰乱脂肪生物学从而引发胰岛素抵抗中的作用尚未得到研究。目标是 这一应用的目的是证明，女性体内过多的睾丸素容易导致代谢 通过作用于AR并在胰腺细胞和脂肪细胞中引发氧化应激而导致综合症和T2 DM。 本申请的具体目的是：通过使用AR基因敲除小鼠来演示 (阿尔科)在女性中，AR细胞中睾丸激素过度激活会引发胰岛素缺乏性糖尿病。 我们将检验这一假说，即AR细胞中过多的睾酮激活会引发氧化应激。 我们将使用脂肪细胞AR基因敲除小鼠(Farko)来确定，在雌性小鼠中，过量的睾丸素 脂肪细胞中AR的激活改变了脂肪细胞因子的分泌，并引发全身炎症和 胰岛素抵抗。最后，我们将使用Farko雌性小鼠和过量的脂肪细胞来验证这一假设 睾酮对脂肪细胞中AR的作用会引发氧化应激，并扰乱脂肪细胞因子的产生。 这些研究的成功完成将有助于将AR定义为高雄激素女性的靶点。这 将帮助这一中心项目实现其支持研究以改善妇女健康的目标。