Grant: Operating 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 a new potential target that is elevated with high glucose in ischemic muscles of rodent animals called SHP-1. SHP-1 is a protein and member of the phosphatase family, that downregulates the activity of important growth factors which have crucial impact on growth factor actions and cell survival. We propose to study the mechanism of SHP-1 activation 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. To accomplish this aim, we will use genetically modified vascular specific mice of SHP-1 to characterize its cellular mechanisms implicated in collateral vessel formation. Several molecular tools to specifically manipulate SHP-1 protein expression levels in endothelial cells and smooth muscle cells will be used to elucidate the molecular interaction of SHP-1 with vascular growth factors. 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 type 1 and 2 diabetes.