THOMAS JEFFERSON UNIVERSITY
Grant: $238,964 - National Institutes of Health - Aug. 1, 2009
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Award Description: Research
Project Description: Therefore, we hypothesize that mice lacking arrestin-2 will have defects in thrombus formation in vivo, particularly in models that are selectively thrombin-dependent. Supplementary Aim I is to characterize thrombus formation in arrestin2-/- mice in thrombin-dependent models of arterial and venous thrombosis. Both the laser injury model of arterial thrombosis and a stasis model of venous thrombosis are thrombin-dependent. Therefore, arrestin2-/- mice will be evaluated relative to wildtype control mice in thrombin-dependent models of venous and arterial thrombosis. As part of the parent grant, we have also been evaluating the ser-thr kinase, GSK3beta, as an effector of Akt in platelets. Our recently published studies show that GSK3beta negatively regulates platelet activation and thrombosis, but the mechanisms by which it controls platelet activation remain undefined. Preliminary data show that treatment of platelets with GSK3beta inhibitors causes them to extend filopodia on fibrinogen, a function regulated by integrin outside-in signaling. The NFkB family member, Bcl-3, has previously been shown to regulate outside-in signaling by integrin alphaIIb-beta 3 in platelets. We show that inhibition of GSK3 activity or deletion of GSK3beta inhibits the phosphorylation and degradation of Bcl-3 in platelets. Therefore, Supplementary Aim II is to determine whether Bcl-3 controls platelet signaling and function downstream of GSK3beta. The supplementary funds will enable hiring of a FTE to conduct the arterial and venous thrombosis assays and the acquisition of the Bcl-3 mice to further our study of how GSK3beta regulates outside-in signaling to the actin cytoskeleton. These Aims will further our understanding of how these Akt pathways are regulated in platelets and are encompassed within the Aims of the parent grant.
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