Insulin Signaling Defects in PCOS

描述（由申请人提供）：该申请代表了R01-DK073632“PCOS中的胰岛素信号缺陷”的竞争性修订，并且正在提交以响应通知no - od -09-058“NIH宣布竞争性修订申请的恢复法案资金可用性”。胰岛素抵抗发生在约70%的PCOS女性患者中，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。多囊卵巢综合征脂肪细胞表现出葡萄糖运输缺陷，这可能是由于我们在多囊卵巢综合征中发现的糖原合成酶激酶3 （GSK3）磷酸化改变所致。在本研究中，我们提出确定异常GSK3活性对IR信号和葡萄糖转运缺陷的贡献，并确定影响IRS/ pi3激酶/Akt级联的异常胰岛素信号是否发生在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确定多囊卵巢综合征胰岛素抵抗的分子机制和信号级联。我们发现GSK3上游抑制Wnt信号通路的基因在PCOS脂肪组织中被上调，这表明Wnt信号的减少可能是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通路组分的表达发生了变化。这两种途径都介导了IL-6的信号传导，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也影响脂肪形成，其缺陷已被发现可增加胰岛素抵抗。在这一竞争性修订中，我们建议确定通过MAPK途径改变的IL-6信号Wnt信号对PCOS与对照脂肪细胞中脂肪形成、葡萄糖运输和PI3K/Akt胰岛素信号通路的影响。这些研究途径是本项目的自然延伸，将对多囊卵巢综合征胰岛素抵抗的机制和途径产生有价值的见解。这些研究将需要雇用额外的工作人员，并购买新的显微镜来研究脂肪形成。

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