The overall objective of this proposal is to use variation among inbred mouse strains in atherosclerosis susceptibility to identify cell types and genes that contribute to the development of atherosclerosis. On the apoE-deficient (apoE-/-) background, mouse strain C57BL/6J (B6) develops much larger atherosclerotic I lesions than strain C3H/HeJ (C3H), despite the fact that two strains have comparable plasma lipid levels when fed a chow diet. F1 hybrids, like their C3H parent, exhibit high resistance to atherosclerosis. We I previously observed that endothelial cells from the aorta of B6 exhibit dramatic induction of inflammatory and I oxidative stress genes in response to oxidized LDL, whereas endothelial cells from C3H exhibited minimal induction. Furthermore, in recombinant inbred strains derived from B6 and C3H, endothelial responses to oxidized LDL cosegregated with atherosclerotic lesion area. Thus, we hypothesize that a dominant genetic variation that modulate the response of arterial wall cells to oxidized LDL contributes to the resistance of C3H to atherosclerosis.
In Specific Aim 1, reciprocal aorta transplantation will be performed to determine the role of the arterial wall in control of atherosclerosis susceptibility. To avoid engraft rejection, C3H.SW, a congenic strain of C3H/HeJ that carries the same MHC haplotype, H-2b, as B6, will be used for transplantation. A segment of recipient infrarenal aorta will be replaced with donor aorta using an end-to-end anastomosis. Atherosclerotic lesion formation in transplanted aorta will be assessed by light microscopy.
In specific Aim 2, we will test the hypothesis that monocytes/macrophages are not responsible for the differential susceptibility by bone marrow transplantation. Reciprocal bone marrow transplantation will be carried out with B6.apoE-/- and C3H.SW.apoE-/- mice. Atherosclerotic lesions at the aortic root of the mice will be measured.
In Specific Aim 3, we will determine the chromosomal locations of genes that modulate atherosclerotic lesions, using an F2 cross derived from the two apoE-/- strains.
In Specific Aim 4, we will conduct molecular analysis to characterize the causative genes residing in the chromosomal regions that influence atherosclerotic lesion formation. ? ?
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