Atherosclerotic coronary heart disease (CHD) is the number one public health problem in the United States. CHD has been increasing in prevalence and with the aging of the baby boomers and the increase in major cardiovascular risk factors in the population (smoking, obesity and physical inactivity) over the last 10 years the problem will be even worse in the 21st century. This is not just a U.S. problem, but is occurring world wide. The WHO has recently predicted that by 2020 heart disease will replace infectious disease worldwide as the number one cause of disability expressed as years of healthy life lost to death or disease. CHD is considered a complex genetic disease with many genes involved and important gene-environment interactions. Cross cultural studies and human and animal feeding studies have clearly established a role for diet, particularly a high saturated fat, high cholesterol diet in atherosclerosis susceptibility. However, clinical studies have also established that there is great variation between people in diet responsiveness of their plasma lipoprotein pattern and presumably, although it has not been studied directly in humans, dietary effects on atherosclerosis susceptibility. Thus a better understanding of gene diet interactions as they effect lipoprotein levels and atherosclerosis susceptibility should lead to better ways to identify and treat individuals susceptible to CHD in the population. In the current competing renewal, I propose to use induced mutant mouse models to better understand the regulation of dietary cholesterol absorption and how dietary fats influence atherosclerosis susceptibility. The following specific aims are proposed: Determine the mechanism of regulation of dietary cholesterol absorption through the study of mutant mice; positional cloning of genes that regulate dietary cholesterol absorption by interbreeding mouse strains that differ in dietary cholesterol absorption; determine the effects of diets enriched in carbohydrate, saturated fat, monounsaturated fat, or polyunsaturated fat on atherosclerosis susceptibility and the mechanisms of the dietary effects observed using induced mutant mouse models of atherosclerosis.
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