H2 haplotype and atherosclerosis

描述（由申请人提供）：辐射是动脉粥样硬化性心血管疾病的危险因素。然而，人们对辐射增强动脉粥样硬化的机制知之甚少。我们最近的研究已经确定H2，即小鼠MHC，是辐射增强动脉粥样硬化易感性的主要遗传决定因素。C3H/HeJ （C3H）小鼠对动脉粥样硬化具有很强的抵抗力，在缺乏载脂蛋白E （apoE-/-）或喂食致动脉粥样硬化饮食时，C57BL/6 （B6）小鼠的病变要小得多。这两个菌株的H2单倍型不同，B6有H2b， C3H有H2k。C3。SW-H2b/SnJ （C3.SW）是C3H/HeJ的同源菌株，其中H2k位点被H2b取代。令人惊讶的是,C3.SW。在致死性照射后进行骨髓移植的apoE-/-小鼠，其动脉粥样硬化病变的大小比C3H增加了21倍。apoE-/-小鼠接受相同的治疗，证明H2单倍型对动脉粥样硬化的显著影响。我们将使用这本新奇的C3.SW。apoE-/-小鼠模型研究H2单倍型与斑块形成之间的机制联系。我们还将在H2区测试一个有希望的候选基因。MDC1编码DNA损伤检查点1的中介，是DNA双链断裂激活的基因组监测网络的一个组成部分。在MDC1的H2b和H2k单倍型之间的编码区和调控区都检测到多个snp。我们将确定MDC1缺乏是否会促进放疗后动脉粥样硬化。这些研究将揭示控制动脉粥样硬化易感性的新基因和新途径。

DESCRIPTION (provided by applicant): Radiation is a risk factor for atherosclerotic cardiovascular disease. However, little is known about the mechanisms that underlie radiation-enhanced atherosclerosis. Our recent studies have identified H2, the murine MHC, as a major genetic determinant of susceptibility to radiation-enhanced atherosclerosis. C3H/HeJ (C3H) mice are extremely resistant to atherosclerosis, developing much smaller lesions than C57BL/6 (B6) mice when deficient in apolipoprotein E (apoE-/-) or fed an atherogenic diet. The two strains differ in the H2 haplotype with B6 having H2b and C3H having H2k. C3.SW-H2b/SnJ (C3.SW) is a congenic strain of C3H/HeJ in which the H2k locus is replaced with H2b. Surprisingly, C3.SW.apoE-/- mice that underwent bone marrow transplantation after lethal irradiation exhibited a 21-fold increase in atherosclerotic lesion size relative to C3H.apoE-/- mice receiving the same treatment, demonstrating the dramatic impact of H2 haplotypes on atherosclerosis. We will use this novel C3.SW.apoE-/- mouse model to investigate mechanistic links between H2 haplotypes and plaque formation. We will also test a promising candidate gene in the H2 region. MDC1, encoding the mediator of DNA damage checkpoint 1, is a component of the genome surveillance network activated by DNA double-strand breaks. Multiple SNPs have been detected in both coding and regulatory regions of MDC1 between H2b and H2k haplotypes. We will determine whether deficiency in MDC1 would promote atherosclerosis following radiation. These studies will shed light on new genes and new pathways that control atherosclerosis susceptibility.