The long term goal of this laboratory is to identify genetic differences in atherosclerosis susceptibility among inbred mouse strains, to map these genes, to identify the gene products, and to elucidate their roles in the atherosclerotic process.
The specific aims of this proposal; are to characterize and map six traits affecting atherosclerosis susceptibility, each of which has some evidence suggesting that the trait is determined by a single gene. These six variants include two (Ath-1, and Ath-2) that affect high density lipoprotein (HDL), one (Ath-5) that affects very low density lipoprotein (VLDL), and three (Ath-6, Ath-7, Ath-8) that affect susceptibility to atherosclerosis without any lipoprotein difference that cosegregates with susceptibility to atherosclerosis among recombinant inbred strains. Ath-1 has already been mapped to a 3 cM region on Chr 1, and in this proposal will be mapped using an interspecific cross to within 0.2 cM, close enough for positional cloning. Ath 2 is tentatively located on Chr 9, and this position will be tested using a congenic at N5 that has the resistant allele of Ath-2 from strain AXB-5 in C57BL/6. A backcross of this congenic to C57BL/6 will be evaluated for cosegregation of atherosclerosis resistance and strain A-like alleles on Chr 9. If Ath-2 is not located on Chr 9, the congenic will be tested for other A-alleles and each A-like regions tested for cosegregation with atherosclerosis in the backcross. Ath-5 is a difference between strains AKR and DBA/2 in the levels of VLDL. It will be mapped by typing loci in the AKXD RI set so that it is completely typed, by finding tentative locations for the trait in the RI set, and by testing these in the backcross. Ath-6 differs between C57BL/6 and C57BL/Ks and is determined by a single gene with smaller lesion size dominant as shown by the distribution of the trait in 37 F2 progeny. The F2 cross is being expanded by another 60 mice in order to carry out the mapping of Ath-6 by testing for all DBA/2-like regions, which constitute 25% of the C57BL/Ks genome. The BXD RI strain set will also be examined to determine whether lesion formation in that RI set can be explained by segregation of Ath-1 and Ath-6 alleles. Ath-7 is a difference between SWR and SJL. Characterizing and mapping this trait requires typing loci in the SWXJ RI set. Ath-8 is a difference in atherosclerosis susceptibility that differs between strains NZB and SM. Segregation in backcross suggests that Ath-8 is determined by a single gene, and the strain distribution of alleles in the NXSM RI set suggests 3 possible locations for this gene.
Showing the most recent 10 out of 44 publications
