Regulation of atherosclerosis susceptibility.

描述（由申请人提供）：本提案的总体目标是利用近交小鼠品系在动脉粥样硬化易感性方面的差异来鉴定有助于动脉粥样硬化发展的细胞类型和基因。在载脂蛋白e缺乏（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，尽管两种品系在饲喂鼠粮时具有相当的血脂水平。F1杂交种和它们的C3H亲本一样，对动脉粥样硬化表现出很高的抵抗力。我们之前观察到，来自B6主动脉的内皮细胞对氧化LDL的反应表现出强烈的炎症和氧化应激基因诱导，而来自C3H的内皮细胞则表现出最小的诱导。此外，在B6和C3H衍生的重组自交系中，内皮细胞对氧化LDL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LDL反应的显性遗传变异有助于C3H对动脉粥样硬化的抵抗。在Specific Aim 1中，我们将进行反向主动脉移植，以确定动脉壁在控制动脉粥样硬化易感性中的作用。为了避免移植排斥反应，C3H。SW是C3H/HeJ的一种同源菌株，携带与B6相同的MHC单倍型H-2b，将用于移植。使用端到端吻合术将一段受体肾下主动脉替换为供体主动脉。移植主动脉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Aim 2中，我们将验证单核细胞/巨噬细胞不负责骨髓移植差异敏感性的假设。骨髓移植将与B6一起进行。apoE-/-和C3H.SW。apoE - / -小鼠。测量小鼠主动脉根部的动脉粥样硬化病变。在特异性目标3中，我们将使用来自两个apoE-/-菌株的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Specific Aim 4中，我们将进行分子分析，以表征存在于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.