Aging, Atherosclerosis, and the Arterial Wall

描述(由申请人提供)：衰老被认为是动脉粥样硬化的主要危险因素，其机制尚不清楚。与传统的危险因素无关，衰老似乎以一种被认为易患动脉粥样硬化的方式影响动脉壁结构。这个项目的目标是研究动脉壁老化导致动脉粥样硬化的机制，并开发一种研究这一过程中重要基因的方法。其中一个这样的基因编码肿瘤坏死因子-a受体-1(TNFR1)，与年轻大鼠相比，它可能介导了老年大鼠主动脉平滑肌细胞对肿瘤坏死因子-α(TNF-α)的增殖性增强。在老年患者中，血清肿瘤坏死因子水平与心肌梗死风险和死亡风险相关。该项目将检验两个假设：(1)动脉壁的老化有助于动脉粥样硬化的形成，与免疫系统的老化无关；(2)动脉壁的肿瘤坏死因子受体以一种通过或增强衰老效应的方式促进动脉粥样硬化的形成。为了验证这些假设，我们将对年轻的载脂蛋白E缺陷(APOE-/-)小鼠进行颈动脉间置移植，这些小鼠发展为颈动脉粥样硬化。移植物将是来自同源基因的年轻和老年小鼠的颈动脉，这些小鼠要么是野生型，要么是(B)缺乏TNFR1。通过比较4组动脉粥样硬化的时程、程度、斑块细胞组成和部分分子变量，我们将评估动脉壁老化和TNFR1在动脉粥样硬化形成中的作用。为了提供衰老和TNFR1对动脉粥样硬化影响的可能机制的证据，我们将对我们的颈动脉供体小鼠的主动脉进行全基因组转录图谱分析：年轻和老年，TNFR1缺陷和野生型。因此，该项目将(A)创建一个模型系统，可以测试动脉壁老化本身是否有助于动脉粥样硬化的形成；(B)阐明动脉壁TNFR1在动脉粥样硬化形成中的作用，无论是在衰老背景下还是在老龄化背景下；(C)创建一个全面的候选基因清单，这将有助于设计机制假说来理解衰老依赖的动脉粥样硬化--可以在我们的颈动脉移植系统中测试的假说。通过这样做，这个项目应该为识别多种动脉壁基因产物奠定基础，这些基因产物要么有助于或防止衰老导致动脉粥样硬化的影响，要么确定新的治疗动脉粥样硬化的可能性。

DESCRIPTION (provided by applicant): Aging is considered a leading risk factor for atherosclerosis, through mechanisms that remain unclear. Independent from traditional risk factors, aging appears to affect arterial wall structure in a manner believed to predispose to atherosclerosis. The goal of this project is to investigate mechanisms by which aging of the arterial wall contributes to atherosclerosis, and to develop an approach for studying the genes important to this process. One such gene encodes the tumor necrosis factor-a receptor-1 (TNFR1), which may mediate the enhanced proliferative responsiveness to TNF-a (TNF) observed in aortic smooth muscle cells from aged, as compared with young rats. Serum levels of TNF have been related to the risk of myocardial infarction and to the risk of mortality in aged patients. This project will test two hypotheses: (1) that aging of the arterial wall contributes to atherogenesis, independently of immune system aging; (2) that arterial wall TNF receptors contribute to atherogenesis, in a manner potentiated by or potentiating the aging effect. To test these hypotheses, we will perform carotid interposition grafting in young apolipoprotein E-deficient (Apoe-/-) mice, which develop carotid artery atherosclerosis. The grafts will be carotid arteries derived from congenic young and aged mice that are either (a) wild type or (b) TNFR1 -deficient. By comparing the atherosclerosis time course, extent, plaque cellular composition and selected molecular variables in these 4 groups, we will assess the role of arterial wall aging and TNFR1 in atherogenesis. To provide evidence for possible mechanisms underlying the effects of aging and TNFR1 on atherosclerosis, we will perform genome-wide transcriptional profiling on aortas from our carotid donor mice: young and aged, TNFR1- deficient and wild type. Thus, this project will (a) create a model system that can test whether arterial wall aging, by itself, contributes to atherogenesis; (b) elucidate the role of arterial wall TNFR1 in atherogenesis, both within and outside of the aging context; (c) create a comprehensive list of candidate genes that will facilitate devising mechanistic hypotheses to understand aging-dependent atherosclerosis-hypotheses that can be tested in our carotid graft system. In so doing, this project should build a foundation for identifying multiple arterial wall gene products that either contribute to or protect against atherosclerosis-predisposing effects of aging, and identify new therapeutic possibilities for atherosclerosis.