The long term goals are to examine genetic factors affecting susceptibility to coronary hear disease in the mouse. The strategy is to select pairs of strains which differ in atherosclerosis susceptibility and which are progenitors of recombinant inbred (RI) strains. These parental strains have been examined for biochemical differences in lipoproteins or apolipoproteins. The segregation of atherosclerotic lesion formation on a high fat diet and the biochemical differences will be tested in each RI set. The resulting data will be used to determine 1) Whether differences in both the atherosclerosis susceptiblity and lipoprotein phenotypes are determined by single genes, 2) the tentative map position of any gene found, and 3) which biochemical differences cosegregate with lesion formation. Tentative map positions will be confirmed by a genetic cross or by analysis of an congenic strain if one is available for that region. As each gene that determines susceptibility to atherosclerosis is defined, we will construct a congenic by placing the resistant allele of that gene on a C57BL/6 background. The construction of congenic strains will greatly facilitate futrue studies on the physiology and the mechanism of action of each gene. This strategy was used during the previous grant period to define two genes, Ath-1 and Ath-2 that act by determining HDL levels. This proposal has four major goals. The first is to develop additional methodology that will be useful in characterizing strains for differences in the lipid transport system. The second is to complete the analysis of HDL variants. This includes further studies on Ath-1, Ath-2, and strain Peru, which appears to carry unique variants in both HDL quantity and size. The third goal is to analyze 4 pairs of RI progenitor strains which differ in the LDL and VLDL components of the lipid transport system. These RI sets differ in levels of apo E (AKR x DBA/2), apo B48 (129 x A), or apo B100 (NZB x 129), or in the response of LDL and VLDL to a high fat diet (C57BL/6 x DBA/2). The fourth goal is to examine 2 sets of RI strains whose parents differ in atherosclerosis susceptibility but do not differ in lipoproteins or apolipoproteins. These strains (SWR x SJL; 129 x C57BL/6) may differ in genes that act by some mechanism other than altering lipoprotein levels.
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