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风险因素，其机制尚不清楚。独立于传统的危险因素，老化似乎影响动脉壁结构的方式被认为是易患动脉粥样硬化。该项目的目标是研究动脉壁老化导致动脉粥样硬化的机制，并开发一种研究该过程重要基因的方法。一个这样的基因编码肿瘤坏死因子-α受体-I（TNFR 1），其可以介导与年轻大鼠相比在来自老年的主动脉平滑肌细胞中观察到的对TNF-α（TNF）的增强的增殖反应。血清TNF水平与老年患者心肌梗死的风险和死亡风险相关。本项目将测试两个假设：（1）动脉壁老化有助于动脉粥样硬化形成，独立于免疫系统老化;（2）动脉壁TNF受体有助于动脉粥样硬化形成，以增强或增强老化效应的方式。为了验证这些假设，我们将在年轻的载脂蛋白E缺陷（Apoe-/-）小鼠，发展颈动脉粥样硬化颈动脉间置移植。移植物将是来自（a）野生型或（B）TNFR 1缺陷的同类年轻和老年小鼠的颈动脉。通过比较这4组中动脉粥样硬化的时间进程、程度、斑块细胞组成和选定的分子变量，我们将评估动脉壁老化和TNFR 1在动脉粥样硬化形成中的作用。为了提供证据的可能机制的影响，老化和TNFR 1动脉粥样硬化，我们将进行全基因组转录谱的动脉粥样硬化从我们的颈动脉供体小鼠：年轻和老年人，TNFR 1缺陷和野生型。因此，该项目将（a）创建一个模型系统，该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形成;（B）阐明动脉壁TNFR 1在动脉粥样硬化形成中的作用，包括老化背景之内和之外;（c）建立一个全面的候选基因清单，以促进设计机制假设，了解衰老依赖性动脉粥样硬化-这些假设可以在我们的颈动脉移植系统中得到验证。在这样做的过程中，这个项目应该建立一个基础，以确定多种动脉壁基因产物，无论是有助于或防止动脉粥样硬化的易感性影响的老化，并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.