Grant Number: 1U01HL70526-01 |
Abstract: Diabetes has complex and far-reaching effects on several end-organ systems. The heart is a particularly prominent target for intervention since the majority of deaths in patients with diabetes result from the combined effects of accelerated coronary artery disease and diabetic cardiomyopathy. To better understand these diabetes-related complications and to develop new therapies, we propose to develop animal models that closely mimic, both pathogenetically and functionally, cardiovascular disease in humans with diabetes. Previous models have largely been naturally occurring strains of mice and rats (e.g. the
non-obese diabetic mouse) or individual transgenics (e.g. the low density lipoprotein receptor null mouse). The primary rationale of our proposal is to now combine specific naturally occurring or induced genetic variations in a systematic manner to produce improved models. In order to efficiently combine naturally occurring variations influencing diabetes-related traits into models, we have developed a new tool, whole-genome congenic strains. We chose the parental strains for this resource on the basis of our quantitative trait locus analyses carried out over the past decade. These analyses revealed numerous loci contributing to body fat, insulin metabolism, inflammation, atherosclerosis, calcification, and stress-induced cardiac myocyte death. These variations will now be bred onto diabetes models, some of which have recently been developed in our laboratories. In particular, the apolipoprotein AIl transgenic mouse develops insulin resistance, hypertriglyceridemia, spontaneous atherosclerosis, increased lipid accumulation in myocytes, and increased body fat. Also, we recently created a mouse deficient for CD68 (a cell surface receptor present on macrophages and dendritic cells) and observed that these animals have defective insulin production, elevated glucose levels, delayed glucose clearance, and preliminary evidence of pancreatic pathology. We will develop these mice as a model for type 1 diabetes. We will also accelerate disease with hypertension and angiotensin II infusion, which will lead to models more closely mimicking human disease associated with target organ sequelae. Our approach should successfully achieve Consortium goals to develop innovative models of diabetes complications mimicking human disease and to test the role of candidate genes or chromosomal regions that arise from human studies, particularly cardiovascular diseases.
Ohio State University-Main Campus|
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