Grant: Project Grant

The mechanisms underlying the progression of poor collateral formation during ischemia in diabetes are not completely understood. High glucose levels have been suggested as one of the most important causal factors of impaired vessel formation characterized by deregulation of growth factor actions causing lower-extremity amputation in patients with diabetes. Our group has made very interesting findings on new potential targets that are regulated by high glucose levels in ischemic muscle of rodent animals called SHP-1 and DUSP4. These proteins are members of the phosphatase family, that downregulates the activity of important growth factors and stress signal pathways which have crucial impact on cell growth and survival. We propose to study the role of SHP-1 and DUSP4 in diabetes causing inhibition of growth factor actions in the formation new capillaries under ischemic condition. The aim of the present proposal will investigate and characterize the contribution of SHP-1 to the incapacity of diabetic animals to generate new blood vessels and how diabetes reduces the expression of DUSP4 leading to cell death. To accomplish this aim, we will use genetically modified mice of SHP-1 and DUSP4 to characterize its cellular mechanisms implicated in collateral vessel formation. Several molecular tools to specifically manipulate SHP-1 and DUSP4 protein expression levels in endothelial and smooth muscle cells will be used to elucidate the role of SHP-1 and DUSP4. We believe that this proposal will provide new insights of the mechanisms underlying poor capillary formation in diabetes. Our research project will offer new mechanistic tools to develop new strategies to promote new blood vessels during ischemia and prevent extremity amputation in diabetic patients.