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: 7929912
• 负责人: FRANK MAUVIS-JARVIS
• 金额: $ 24.31万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7929912
• 关键词: Adipocytes; Age; Androgens; Apoptosis; Biology; Catabolism; Cells; Chronic; Collaborations; Data; Diabetes Mellitus; Endocrine System Diseases; Environment; Fatty acid glycerol esters; Female; Gene Expression; Genes; 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; Research Support; Role; Serum; 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）是生殖女性中最常见的内分泌疾病 美国的年龄是通过慢性炎症，胰岛素实现的超雄激素的PCOS 电阻和2型糖尿病（T2DM）。该提议中提出的证据表明，在妇女和 超过睾丸激素产生的小鼠会产生感染，从而改变了脂肪生物学和胰岛素的产生， 因此有助于胰岛素抵抗，代谢综合征和T2DM。尽管有这些观察， 缺乏睾丸激素直接改变胰岛分泌的证据缺乏胰岛素的分泌，并且缺乏胰岛素的作用，并且作用 尚未研究睾丸激素破坏脂肪生物学，从而引起胰岛素抵抗。目标 此应用的是证明，女性的睾丸激素超过了代谢 综合征和T2DM通过作用于胰腺和脂肪细胞中的AR和引发氧化应激。 该应用程序的具体目的是：通过使用� -cell arnockout鼠标来证明 （Arko）在女性中，超过AR睾丸激素在�-细胞中会引起胰岛素缺陷型糖尿病。 我们将测试超过AR睾丸激活–细胞激活的假设会引起氧化物的胁迫。 我们将使用脂肪细胞AR基因敲除鼠标（Farko）来确定在女性中超过睾丸激素 脂肪细胞中AR的激活改变了脂肪细胞因子的分泌，并引发系统注射和 胰岛素抵抗。最后，我们将使用超过的farko雌性小鼠和脂肪细胞检验假设 睾丸激素对脂肪细胞中AR的作用会引起氧化应激，并破坏脂肪细胞因子的产生。 这些研究的成功完成将有助于将AR定义为超雄激素女性的靶标。这 将帮助该中心计划实现支持研究以改善妇女健康的目标。