The long term goal is to identify molecular mechanisms for the onset of accelerated atherosclerosis in diabetes mellitus. This will be accomplished by studying animal models susceptible to both diabetes and atherosclerosis. The investigators have now developed several mouse models which show accelerated atherosclerosis upon becoming diabetic. These include the BALB/c strain treated with streptozotocin and fed a high fat/cholesterol diet, and diabetic NOD mice. These and other mouse strains will be used to identify genetic and environmental factors influencing atherosclerosis due to the diabetic state, and to explore possible steps toward treatment or prevention of atherosclerosis disease in diabetics. There are four specific aims.
The first aim i s to characterize lesion cellular composition and vascular sites of development. Immunocytochemical and histological approaches will be used. The hypothesis is that diabetes induces differences in lesion composition and location in the vasculature.
The second aim i s to identify biochemical pathways through which hyperglycemia and dyslipidemia enhance oxidation at the artery wall and in model tissues using gas chromatography/mass spectroscopy and specific antibodies. The investigators hypothesize a role for oxidation in accelerated atherosclerosis.
The third aim i s to determine whether hyperglycemia and dyslipidemia alter the expression of inflammatory genes and matrix molecules at the artery wall and in model tissues. Gene expression will be studied at the level of mRNA and protein in artery wall and liver tissues.
The fourth aim i s to determine whether atherosclerosis can be ameliorated by treatment with insulin and/or dietary anti-oxidants. In summary, the investigators have created a panel of mouse models which can be compared and contrasted as to the mechanisms leading to atherosclerosis onset in the diabetic state. Studies will also be initiated toward identifying treatments to retard or reverse atherosclerosis in diabetics.
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