Insulin Signaling Defects in PCOS

PCOS 中的胰岛素信号缺陷

基本信息

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
项目类别：
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

项目摘要

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 R01-DK073632“PCOS 中的胰岛素信号缺陷”的竞争性修订，并根据通知 NOT-OD-09-058“NIH 宣布恢复法案资金用于竞争”而提交。修订申请”。约 70% 的 PCOS 女性出现胰岛素抵抗，我们的数据表明，这可能是由于胰岛素受体 (IR) 下游磷脂酰肌醇 3-激酶 (PI3K)/Akt 信号级联的改变所致。 PCOS 脂肪细胞表现出葡萄糖转运缺陷，这可能是由于我们在 PCOS 中发现的糖原合酶激酶 3 (GSK3) 的磷酸化改变所致。在我们的母基金中，我们提议确定异常 GSK3 活性对 IR 信号传导和葡萄糖转运缺陷的影响，并确定影响 IRS/PI3 激酶/Akt 级联的异常胰岛素信号传导是否发生在 PCOS 脂肪细胞中。在我们的研究过程中，我们开始使用微阵列分析来识别可能与 PCOS 胰岛素抵抗相关的分子机制和信号级联。我们发现抑制 GSK3 上游 Wnt 信号通路的基因在 PCOS 脂肪组织中上调，这表明 Wnt 信号通路的减少可能是 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 通路成分的表达发生变化。这两条途径均介导 IL-6 信号传导，IL-6 是一种促炎细胞因子，我们发现它可以减少 PCOS 脂肪细胞中的葡萄糖转运。 Wnt 和 IL-6 也会影响脂肪生成，脂肪生成缺陷被发现会增加胰岛素抵抗。在本次竞争性修订中，我们建议确定 PCOS 与对照脂肪细胞中通过 MAPK 途径改变的 IL-6 信号 Wnt 信号对脂肪生成、葡萄糖转运和 PI3K/Akt 胰岛素信号途径的影响。追求这些代表了母基金范围的自然扩展的研究途径，将为了解多囊卵巢综合征胰岛素抵抗的机制和途径提供有价值的见解。这些研究将需要雇用更多的工作人员，以及购买新的显微镜来研究脂肪生成。公共卫生相关性：本次修订通过以下方式满足了《复苏法案》的目标：允许雇用更多员工；避免解雇关键人员；并能够购买额外所需的设备。此外，我们预计，通过提高现有研究的速度，该增刊将使我们能够为未来的提交奠定基础，这有可能既确保现有工作岗位，又创造新的工作岗位