The objectives of this SERCA award proposal are for the candidate, Andrew C. Nicholson, D.V.M., to develop expertise in basic scientific disciplines (molecular biology, biochemistry, and cell biology) to compliment his previous training in veterinary medicine and comparative pathology. The proposed research will be performed in the laboratory of Dr. David P. Hajjar who is acting as the scientific advisor for this project. The scientific environment for the proposed studies, Cornell University Medical College, will provide state-of-the-art equipment and facilities, and will allow the candidate to interact with researchers (D.V.M., M.D., and Ph.D) with a breadth of expertise in basic and clinical sciences. This training period will facilitate the use of a multidisciplinary approach toward the study of an animal model for an important human health problem, atherosclerosis. Atherosclerosis and its complications are the major cause of mortality in the United States. In humans and animal models of atherosclerosis, the earliest lesion (fatty streak) results from the accumulation of lipid within macrophages of the subendothelial space. In later stages of the lesion, both macrophages and smooth muscle cells (SMC) have become cholesteryl ester (CE-laden """"""""foam cells"""""""" and are a characteristic feature of the atherosclerotic plaque. The accumulation of CE within these foam cells is though to be due to alterations in the delivery (binding and internalization), intracellular metabolism, and efflux, which will ultimately determine the extent of lipid accretion by these cells. Binding and internalization of lipoproteins is mediated by specific receptors for LDL (the LDL receptor) and modified forms of lipoprotein (the scavenger receptor). Cytokines and growth factors produced by vascular and inflammatory cells of the atherosclerotic plaque may be important modulators of the expression of these receptors and the subsequent intracellular metabolism of these lipids. The scientific objective of this SERCA Award proposal will be to determine the effects of cytokines and growth factors on the regulation of macrophage and SMC lipoprotein and modified lipoprotein receptors; and to define the role of eicosanoids as mediators of cholesterol trafficking in response to these soluble mediators; and to evaluate the in vivo expression of the LDL and scavenger receptors in rabbit models of human dietary induced atherosclerosis and familial hypercholesterolemia. Experiments described in this research proposal will provide valuable information on the expression of lipoprotein and modified lipoprotein receptors. A comprehensive understanding of the regulation of the binding and metabolism of LDL and modified LDL will help in devising strategies to modulate the accretion of lipid within the vessel wall. Expertise developed during the training and research periods of this grant will allow the candidate to develop as an independent investigator, with unique qualifications to effectively utilize laboratory animals for biomedical research.
