Molecular Regulation of CC Chemokine in Atherosclerosis and Aging

CC趋化因子在动脉粥样硬化和衰老中的分子调控

• 批准号: 7123665
• 负责人: RAYMOND L YUNG
• 金额: $ 33.38万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7123665
• 关键词: DNA methylation; aging; apolipoprotein E; atherosclerosis; cell surface receptors; chemokine; chemokine receptor; chemotaxis; clinical research; coronary disorder; flow cytometry; genetic promoter element; genetically modified animals; human subject; laboratory mouse; methyltransferase; microarray technology; molecular pathology; monocyte; pathologic process; patient oriented research; receptor expression; transcription factor; transfection; western blottings

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.

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非常差。目前还不清楚所报道的炎症介质的年龄相关变化是否独立于年龄相关疾病发生，或者是对它们的反应。动脉粥样硬化被描述为“典型的年龄相关疾病过程”。然而，老年人冠状动脉疾病高患病率的原因尚不清楚。T细胞和单核细胞趋化因子受体最近成为介导动脉粥样硬化炎症反应的关键因素。我们最近还报道称，衰老与选定的CC趋化因子受体（包括CCR 2和CCR 5）的基因表达增加有关。该项目的长期目标是改善老年人冠状动脉疾病的护理。该提案的具体目标是解决衰老与白细胞C-C趋化因子受体表达增加相关的假设，该白细胞C-C趋化因子受体表达增加是由C-C趋化因子受体启动子的年龄相关的低甲基化引起的，由此产生的白细胞趋化因子受体表达增加反过来有助于老年人冠状动脉疾病的高患病率。具体目标1将在基因（微阵列，核糖核酸酶保护测定），蛋白质（Western印迹，流式细胞术）和功能（趋化性测定）水平上定义正常人类衰老和老年冠状动脉疾病中T细胞和单核细胞趋化因子受体的表达和功能。具体目标2将使用体外转染、亚硫酸氢盐测序和补丁甲基化来确定启动子甲基化在老年冠状动脉疾病中白细胞趋化因子受体（CCR 1，2，5，8）表达中的作用。具体目标3将通过将载脂蛋白E缺陷（apoE-/-）小鼠与趋化因子受体和DNA甲基转移酶1敲除动物杂交来确定趋化因子受体缺陷和DNA低甲基化对衰老中动脉粥样硬化的体内进展的影响。 与公共卫生的相关性：虽然仅占美国人口的13%，但65岁以上的患者占所有急性心肌梗死（MI）的60%以上和所有MI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快速老龄化的美国人口的护理，并可能导致新的治疗方法。