Regulation of atherosclerosis susceptibility

描述（由申请人提供）：本提案的总体目标是利用动脉粥样硬化易感性近交系小鼠品系之间的变异来鉴定有助于动脉粥样硬化发展的细胞类型和基因。在apoE-缺陷（apoE-/-）背景下，小鼠品系C57 BL/6 J（B6）比品系C3 H/HeJ（C3 H）发展更大的动脉粥样硬化I病变，尽管事实上两个品系在喂食普通饲料时具有相当的血浆脂质水平。F1杂种，像它们的C3 H亲本一样，表现出对动脉粥样硬化的高抗性。我们以前观察到，内皮细胞从主动脉的B6表现出显着的诱导炎症和I氧化应激基因在氧化低密度脂蛋白的反应，而内皮细胞从C3 H表现出最小的诱导。此外，在B6和C3 H衍生的重组近交系中，内皮细胞对氧化LDL的反应与动脉粥样硬化病变面积共分离。因此，我们假设，一个显性的遗传变异，调节动脉壁细胞的反应，氧化低密度脂蛋白有助于抗C3 H动脉粥样硬化。在特定目标1中，将进行相互主动脉移植，以确定动脉壁在控制动脉粥样硬化易感性中的作用。为了避免移植物排斥，将使用C3H.SW（一种携带与B6相同的MHC单倍型H-2b的C3 H/HeJ同源株）进行移植。采用端对端吻合术，将受体肾下主动脉的一段替换为供体主动脉。将通过光学显微镜评估移植主动脉中的动脉粥样硬化病变形成。在具体目标2中，我们将检验单核细胞/巨噬细胞不负责骨髓移植的差异敏感性的假设。将对B6.apoE-/-和C3H.SW.apoE-/-小鼠进行相互骨髓移植。将测量小鼠主动脉根部的动脉粥样硬化病变。在特定目标3中，我们将使用来自两种apoE-/-菌株的F2杂交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，以表征染色体区域中影响动脉粥样硬化病变形成的致病基因。

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.