Insulin Signaling Defects in PCOS

PCOS 中的胰岛素信号缺陷

• 批准号: 7849274
• 负责人: Ricardo Azziz
• 金额: $ 4.88万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-05 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7849274
• 关键词: 1-Phosphatidylinositol 3-Kinase; Abdomen; Accounting; Adipocytes; Adipose tissue; Affect; Affinity; Aliquot; Androgens; Binding; Compensatory Hyperinsulinemia; Coupled; Data; Defect; Equipment; Etiology; Exhibits; Face; Fibroblasts; Foundations; Funding; Future; Gene Expression; Genes; Glycogen; Glycogen (Starch) Synthase; Glycogen Synthase Kinase 3; Hepatic; Hour; Human Resources; Immunofluorescence Immunologic; Immunoprecipitation; Incubated; Individual; Insulin; Insulin Receptor; Insulin Resistance; Insulin Signaling Pathway; Interleukin-6; Investigation; Lead; MAP Kinase Gene; MAPK Signaling Pathway Pathway; MAPK14 gene; MAPK8 gene; MEKs; Measures; Mediating; Methods; Microarray Analysis; Microscope; Molecular; Muscle; Non obese; Obesity; Occupations; Ovarian; Pathway interactions; Patients; Phosphorylation; Play; Polycystic Ovary Syndrome; Positioning Attribute; Process; Production; Proteins; Publishing; Receptor Signaling; Recovery; Research; Research Personnel; Role; SB 203580; Secure; Serine; Sex Hormone-Binding Globulin; Signal Pathway; Signal Transduction; Skeletal Muscle; Study Subject; Sum; Time; Tyrosine; Tyrosine Phosphorylation; United States National Institutes of Health; Western Blotting; Woman; cytokine; glucose transport; glucose uptake; inhibitor/antagonist; insight; insulin receptor substrate 1 protein; insulin signaling; lipid biosynthesis; meetings; novel; parent grant; public health relevance; receptor; reproductive; response; skills; subcutaneous; theca cell; volunteer

DESCRIPTION (provided by applicant): This application represents a competitive revision to R01-DK073632 'Insulin Signaling Defects in PCOS' and is being submitted in response to Notice NOT-OD-09-058 'NIH announces the availability of Recovery Act Funds for Competitive Revision Applications'. Insulin resistance occurs in ~70% of women with PCOS, which our data suggest may result from alterations in the phosphatidylinositol 3-kinase (PI3K)/Akt signaling cascade, downstream of the insulin receptor (IR). PCOS adipocytes exhibit defective glucose transport, which may result from the altered phosphorylation of glycogen synthase kinase-3 (GSK3) we identified in PCOS. In our parent grant, we proposed to determine the contribution of abnormal GSK3 activity to defects in IR signaling and glucose transport, and to determine whether abnormal insulin signaling affecting the IRS/PI3-kinase/Akt cascade, occurs in PCOS adipocytes. During the course of our studies, we began to use microarray analysis to identify molecular mechanisms and signaling cascades potentially involved in insulin resistance in PCOS. We found that genes that inhibit the Wnt signaling pathway, upstream of GSK3, are up-regulated in PCOS adipose tissue, suggesting that decreased Wnt signaling may underlie the increased GSK activity in PCOS adipocytes. We also found alterations in the expression of components of JAK/STAT and MAPK pathways in PCOS adipose tissue. Both of these pathways mediate signaling by IL-6, a proinflammatory cytokine which we have found to decrease glucose transport specifically in PCOS adipocytes. Both Wnt and IL-6 also affect adipogenesis, defects of which have been found to increase insulin resistence. In this competitive revision, we propose to determine the effects of altered Wnt signaling of IL-6 signaling via the MAPK pathway, on adipogenesis, glucose transport and the PI3K/Akt insulin signaling pathway in PCOS vs. control adipocytes. Pursuing these avenues of investigation, which represent natural extensions of the scope of the parent grant, will yield valuable insights into the mechanisms and pathways underlying insulin resistance in PCOS. These studies will require the hiring of additional staff, as well as the purchase of a new microscope to study adipogenesis. PUBLIC HEALTH RELEVANCE: This revision meets the objectives of the Recovery Act by: enabling the hiring of additional staff; avoiding layoff of key personnel; and enabling the purchase of additional needed equipment. Moreover, we anticipate that by advancing the rate of our existing research, the supplement will enable us to lay the foundations for future submissions, which has the potential to both secure existing jobs and create new ones

描述（由申请人提供）：本申请代表对PCOS中R01-DK073632“胰岛素信号传导缺陷”的竞争性修订，并正在提交以响应通知Not-OD-09-058'NIH宣布恢复ACT资金的可用性用于竞争性修订应用程序。胰岛素抵抗发生在约70％的患有PCOS的女性中，我们的数据表明，这可能是由于胰岛素受体（IR）下游的磷脂酰肌醇3-激酶（PI3K）/AKT信号级联反应的改变。 PCOS脂肪细胞表现出有缺陷的葡萄糖转运，这可能是由于我们在PCOS中鉴定出的糖原合酶激酶3（GSK3）的磷酸化改变所致。在我们的父授予中，我们建议确定异常GSK3活性对IR信号传导和葡萄糖转运缺陷的贡献，并确定是否影响IRS/PI3-激酶/AKT级联反应异常，发生在PCOS脂肪细胞中。在研究过程中，我们开始使用微阵列分析来鉴定有可能参与PCOS中胰岛素抵抗的分子机制和信号级联反应。我们发现，在PCOS脂肪组织中抑制Wnt信号通路（GSK3上游）的基因在PCOS脂肪组织中被上调，这表明Wnt信号降低可能是PCOS脂肪细胞中GSK活性增加的基础。我们还发现PCOS脂肪组织中JAK/STAT和MAPK途径的成分表达发生了变化。这两种途径均通过IL-6介导信号传导，IL-6是一种促炎细胞因子，我们发现它可以降低PCOS脂肪细胞中专门降低葡萄糖的转运。 Wnt和IL-6都会影响脂肪形成，其缺陷被发现增加了胰岛素抵抗。在这项竞争性修订中，我们建议通过MAPK途径确定IL-6信号传导改变WNT信号的影响，对PCOS与控制脂肪细胞中PCOS中的脂肪生成，葡萄糖转运和PI3K/AKT胰岛素信号通路。追求这些代表父授予范围的自然扩展的调查途径将对PCOS中胰岛素抵抗的机制和途径产生宝贵的见解。这些研究将需要雇用额外的员工，以及购买新的显微镜来研究脂肪形成。 公共卫生相关性：此修订符合《恢复法》的目标：启用额外员工；避免裁员关键人员；并能够购买其他所需的设备。此外，我们预计，通过提高现有研究的速度，该补充剂将使我们能够为将来的提交奠定基础，这有可能既可以确保现有工作又创造新的工作