Molecular Regulation of CC Chemokine in Atherosclerosis and Aging

描述(由申请人提供)：已知的年龄相关免疫缺陷与特定疾病或临床结果之间的相关性很差。目前也不清楚所报道的与年龄相关的炎症介质变化是独立于与年龄相关的疾病发生的，还是对这些疾病的反应。动脉粥样硬化被描述为“典型的与年龄相关的疾病过程”。然而，老年人冠状动脉疾病患病率高的原因尚不清楚。近年来，T细胞和单核细胞趋化因子受体已成为动脉粥样硬化炎症反应的关键因子。我们最近还报道，衰老与特定的CC趋化因子受体基因表达增加有关，包括CCR2和CCR5。该项目的长期目标是改善老年人对冠状动脉疾病的护理。该提案的具体目标是解决这一假说，即衰老与白细胞C-C趋化因子受体表达增加有关，这是由与年龄相关的C-C趋化因子受体启动子的低甲基化引起的，从而导致白细胞趋化因子受体表达增加，进而导致老年人冠心病的高发病率。具体目标1将在基因(微阵列、核糖核酸酶保护分析)、蛋白质(Western印迹、流式细胞术)和功能(趋化分析)水平上确定T细胞和单核细胞趋化因子受体在正常衰老和老年冠心病患者中的表达和功能。特异靶向2将通过体外转染、亚硫酸氢盐测序和斑块甲基化来确定白细胞趋化因子受体(CCR1、2、5、8)的启动子甲基化在冠状动脉疾病衰老过程中的作用。通过将载脂蛋白E缺陷(apoE-/-)小鼠与趋化因子受体和DNA甲基转移酶1基因敲除动物杂交，确定趋化因子受体缺陷和DNA低甲基化在体内衰老动脉粥样硬化进展中的作用。 与公共卫生相关：虽然65岁以上的患者只占美国人口的13%，但他们占所有急性心肌梗死(ML)的60%以上，占所有ML死亡的85%。更好地了解衰老在调节冠状动脉疾病炎症反应中的作用将改善对快速老龄化的美国人口的护理，并有可能为其带来新的治疗方法。

DESCRIPTION (provided by applicant): There is a very poor correlation between the known age-associated immune defects and specific disease or clinical outcome. It is also unclear if the reported age-related changes in inflammatory mediators occur independently of age-related diseases, or are a response to them. Atherosclerosis has been described as the 'quintessential age-related disease process'. However, the reason for the high prevalence of coronary artery disease in the elderly is unclear. T cell and monocyte chemokine receptors have recently emerged as critical factors in mediating the inflammatory responses in atherosclerosis. We also recently reported that aging is associated with the increase gene expression of selected CC chemokine receptors, including CCR2 and CCR5. The long term goal of this project is to improve the care of coronary artery disease in the elderly. The specific goal of the proposal is to address the hypothesis that aging is associated with increase leukocyte C-C chemokine receptor expression that is caused by the age-associated hypomethylation of C-C chemokine receptor promoters, with the resulting increased leukocyte chemokine receptor expression in turn contributes to the high prevalence of coronary disease in the elderly. Specific Aim 1 will define the T cell and monocyte chemokine receptor expression and function in normal human aging and in elderly with coronary artery disease, at the gene (microarray, ribonuclease protection assays), protein (Western blot, flow cytometry) and functional (chemotaxis assays) levels. Specific Aim 2 will determine the role of promoter methylation in leukocyte chemokine receptor (CCR1, 2, 5, 8) expression in coronary artery disease in aging using in vitro transfection, bisulfite sequencing, and patch methylation. Specific Aim 3 will determine the effect of chemokine receptor deficiency and DNA hypomethylation on the in vivo progression of atherosclerosis in aging, by crossing the apolipoprotein E deficient (apoE-/-) mice with chemokine receptor and DNA methyltransferase 1 knockout animals. Relevance to public health: While representing only 13% of the US population, patients over the age of 65 years account for more than 60% of all acute myocardial infarctions (Ml) and 85% of all Ml deaths. A better understanding of the role of aging plays in modulating the inflammatory response in coronary artery disease will improve the care of, and potentially lead to novel therapies for, the rapidly aging US population.