Regulation of atherosclerosis susceptibility.

描述(由申请人提供)：这项建议的总体目标是利用近交系小鼠品系中动脉粥样硬化易感性的差异来识别导致动脉粥样硬化发展的细胞类型和基因。在apoE缺失(apoE-/-)的背景下，小鼠品系C57BL/6J(B6)比品系C3H/HeJ(C3H)发生更大的动脉粥样硬化I病变，尽管两个品系在喂养食物时具有相似的血脂水平。F1杂交种，就像它们的C3H亲本一样，表现出对动脉粥样硬化的高抵抗力。我们以前观察到，B6的主动脉内皮细胞对氧化低密度脂蛋白的反应表现出强烈的炎性和氧化应激基因的诱导，而C3H的内皮细胞表现出最小的诱导。此外，在B6和C3H来源的重组近交系菌株中，内皮对氧化低密度脂蛋白的反应与动脉粥样硬化病变区域共分离。因此，我们假设，调节动脉壁细胞对氧化低密度脂蛋白反应的显性遗传变异有助于C3H对动脉粥样硬化的抵抗。在特定的目标1中，将进行相互的主动脉移植，以确定动脉壁在控制动脉粥样硬化易感性中的作用。为了避免移植排斥，C3H.Sw将用于移植，C3H.Sw是C3H/HeJ的同源菌株，携带与B6相同的MHC单倍型H-2b。受者肾下动脉的一段将被供体主动脉替换，采用端到端吻合。移植动脉中动脉粥样硬化病变的形成将通过光学显微镜进行评估。在特定的目标2中，我们将检验单核/巨噬细胞不是骨髓移植分化易感性的原因的假设。B6.apoE-/-和C3H.SW.apoE-/-小鼠将进行双向骨髓移植。将测量小鼠主动脉根部的动脉粥样硬化病变。在具体目标3中，我们将使用来自两个apoE-/-株的F2杂交来确定调节动脉粥样硬化病变的基因的染色体位置。在具体目标4中，我们将进行分子分析，以确定影响动脉粥样硬化病变形成的染色体区域的致病基因。

DESCRIPTION (provided by applicant): 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.