A majority of people with diabetes die of cardiovascular disease caused by atherosclerosis, which is more severe and accelerated by diabetes. Arterial smooth muscle cells (SMCs) are normally contractile and quiescent in the healthy arterial wall. During formation and progression of lesions of atherosclerosis however, SMCs gain the ability to respond to growth factors and to proliferate; a key event in the formation and progression of lesions of atherosclerosis. The cellular mechanisms underlying the atherogenic effects on SMCs in diabetes are not clear, but recent studies have shown that elevated blood glucose is an important predictor of cardiovascular disease in diabetes. The applicant's preliminary studies demonstrate that hyperglycemia markedly stimulates the ability of a distinct population of human SMCs to proliferate in response to growth factors, such as platelet-derived growth factor (PDGF). The investigator proposes to characterize this population of primary, non-transformed, human arterial SMCs. Her preliminary studies also show that the p70 S6 kinase, a signaling molecule known to be required for cell cycle traverse, is activated by hyperglycemia in these cells. Further, inhibition of the p70 S6 kinase pathway completely blocks the ability of hyperglycemia to facilitate PDGF-induced proliferation. She will therefore investigate how hyperglycemia stimulates the p70 S6 kinase and if p70 S6 kinase is required, or even sufficient, for hyperglycemia-induced human SMC proliferation in response to growth factors. The investigator proposes to address these questions by using mutated forms of p70 S6 kinase and other components of this pathway, including the upstream kinase mTOR. She will also study the effects of hyperglycemia and diabetes on populations of arterial SMCs in a recently developed porcine model of diabetes-accelerated atherosclerosis.
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