Basic science training during a receipt of a Ph.D. in biophysics prepared the candidate for a career in biomedical research. Clinical training in geriatrics complemented this foundation, producing a scientist interested in applying basic biochemical skills to study the effects of aging on metabolic risk factors for coronary artery disease (CAD). Research as a fellow suggested that 20 aging processes (disease, physical inactivity and diet) and genetic factors were more important than aging itself in the development of CAD. In a subgroup of older men without apparent risk factors for CAD, silent myocardial ischemia (SI) was attributed to """"""""old age""""""""; however, the candidate discovered subtle abnormalities in high density lipoprotein (HDL) metabolism. This suggested that aging itself was not the only cause of atherosclerosis in these men. Receipt of this award will extend the research training of the applicant to the investigation of the pathophysiology and molecular genetics of dyslipoproteinemia in older men with SI. Dedicated research time will permit the candidate to develop the additional skills in clinical and biomedical research and molecular biology necessary for independent stature as a clinical investigator in aging research. These skills will be taught in the enriched research environment at Johns Hopkins, the National Institutes of Aging, NIH and the Univ. of California.The major hypothesis of this research is that other-wise healthy older men with SI have both genetic and/or acquired abnormalities in the regulation of HDL metabolism by the enzymes hepatic lipase and lipoprotein lipase that reduce HDL6 and Apo A-I levels and increase postprandial lipemia and Apo B enrichment of LDL. This hypothesis will be tested by: (1) Metabolic studies in older men with Sl and in matched normal controls to examine the regulation of HDL metabolism in the fasted and postprandial state; (2) Examining the metabolic responses of patients with SI to low fat/low cholesterol diets or weight loss; and (3) Family studies to evaluate the presence of a genetic dyslipoproteinemia in some men with SI. Analysis of the relationship of HDL to TG-rich lipoprotein and regulatory enzymes may elucidate the mechanisms responsible for the abnormal HDL metabolism. Family studies will determine the presence of a genetic dyslipoproteinemia and may improve the detection of patient at high risk for CAD. Knowledge of the pathogenesis of the lipid abnormalities in men with SI and the responses to nutritional interventions may provide insights into interventions which could potentially retard or reverse the progression of CAD.
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