This proposal is based on the hypothesis that the apolipoproteins play a critical role in the regulation of lipid metabolism and that these abnormalities in lipid metabolism are important etiologic factors in the pathogenesis of atherosclerosis. Very recently, completed studies in our laboratory have demonstrated that patients with coronary artery disease who have lesions on angiography demonstrating greater than 50% stenosis of one or more coronary arteries have a 90-95% incidence of abnormally low levels of apolipoprotein A-I. Additional, recent studies in our laboratory suggest that the administration of apolipoprotein A-I to cholesterol-fed rabbits, who also have a deficiency of apolipoprotein A-I in their plasma, markedly reduces the development of aortic atherosclerosis. Additional studies by our group during the past two years have suggested that there are three distinct subgroups of the normal population who have unique apolipoprotein profiles based on the interrelationship of apolipoproteins including apolipoprotein A-I, cholesterol, and triglycerides. This study has been designed to evaluate the effects of genetic factors and a number of environmental factors including exercise, alcohol, and physiologic changes of estrogen levels associated with pregnancy on the levels of apolipoprotein A-I in defined population groups. In addition, we hope to further confirm the relationship of apolipoprotein A-I to the presence of angio-graphically detected coronary artery disease and, finally, by measuring other apoliporoteins in the plasma, we hope to determine whether or not the interrelationship of apolipoprotein A-I with the levels of other apolipoproteins in plasma may further enhance of modify the roles of apolipoprotein A-I in regulating cholesterol accumulation in the artery wall and thus affecting the progression of atherosclerotic lesions. Particular emphasis will be placed on determining the role of genetic determinants in modifying levels of apolipoprotein A-I and in modifying the interrelationship of apolipoprotein A-I levels with the levels of the other major apolipoproteins in the HDL particle. In a further attempt to characterize the roles of these apolipoproteins, monoclonal antibodies will be used as probes in evaluating their immunologic structure and their structure-functional relationships.
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