Since the mayor cause of morbidity and mortality in diabetics is macrovascular disease, we propose creating mouse models in which diabetes worsens macrovascular disease. These models will be of great use for studies of pathophysiology and to design new therapies. To produce such models, we have assembled a multidisciplinary team with expertise in mouse models of diabetes and dyslipidemia and in the evaluation of atherosclerosis progression, atherosclerosis regression/remodeling and injury/restenosis. We propose modern genetic approaches to generate diabetic mouse models in which hyperglycemia can be induced by compromising pancreatic (beta-cell function. This will be accomplished through the conditional expression of dominant-negative mutant forms of HNF-1 alpha or HNF-4 alpha or through the inactivation of HNF-1 beta using beta-cell specific promoters and inducible recombinases in transgenic mice. Mice in which hyperglycemia can be induced will be crossed with genetically manipulated mice that have defects of insulin resistance and /or obesity.
This aim, in a novel way, will establish diabetic animal models that recapitulate the clinical history of the most common form of diabetes, type II, which is characterized by a variable period of insulin resistance/obesity (pre-diabetic state) followed by P-cell decompensation and the development of overt diabetes. A second challenge will be to mimic in the mouse the diabetic dyslipidemia phenotype, which is characterized by increased triglycerides, small dense LDL and decreased HDL cholesterol. Since we have already shown that this is insufficient to cause atherosclerosis in the mouse, we will also breed in traits to raise the levels of LDL cholesterol. To accomplish this we will use human apo CIII and cholesterol ester transfer, protein transgenes and either the human apo B transgene or the LDL receptor knockout trait. Our strategy will be to cross diabetic models with the diabetic dyslipidemia models to establish new models in which diabetes worsens macrovascular disease, as measured by atherosclerosis progression, regression/remodeling, and/or injury/restenosis. We will then use new genetic technology to combine the various required alleles to make a diabetogenic- macrovascular disease model that is easy to breed and transfer to other investigators.
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