The goals of the proposed study include the measurement of metabolic abnormalities of hematopoietic cells in the Watanabe heritable hyperlipidemic (WHHL) rabbit, an animal model of familial hypercholesterolemia (FH) in man, and the determination of the effects of transplantation of normal hematopoietic cells on lipid metabolism and the development of atherosclerosis in the WHHL rabbit. Hematopoietic cells of WHHL rabbits exhibit metabolic abnormalities including the absence of low density lipoprotein (LDL) receptors and abnormal production of proteoglycans which have been implicated in the pathogenesis of atherosclerosis. Using long term bone marrow cultures form normal and WHHL rabbits we plan to more specifically define the abnormalities in LDL metabolism by measuring receptor-dependent metabolism over time. Proteoglycan biosynthesis will be assayed using combinations of DEAE ion exchange chromatography, molecular sieve chromatography, and electron microscopy. We will determine the requirements for the development of complete hematopoietic chimerism in the rabbit following which allogeneic bone marrow transplantation (BMT) between normal NZW rabbit donors and homozygous WHHL rabbit recipients will be carried out. After the construction of complete NZW/WHHL chimeras, we will measure in vivo LDL metabolism in BMT recipients by using a double radioisotope labeling technique to determine the plasma clearance of LDL. We will also determine the impact of transplantation of normal marrow into WHHL recipients by pathologically examining arteries for evidence of atherosclerosis in some recipients and following others for long term survival. The candidate is committed to the establishment of a career in academic medicine as a laboratory-based investigator. The University of Washington faculty provides a unique blend of investigators with expertise in essentially all aspects of the proposed research project; and the facilities at the Fred Hutchinson Cancer Research Center will provide all the necessary equipment for the accomplishment of the proposed research.
