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.
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
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