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

基本信息

批准号：
7640834
负责人：
RAYMOND L YUNG
金额：
$ 31.77万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
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/7640834
关键词：
Accounting Acute myocardial infarction Address Affect Age Age Reporting Aging Apolipoprotein E Applications Grants Arterial Fatty Streak Atherosclerosis Binding Proteins Biological Assay Blood Vessels CCR1 gene CCR5 gene CD28 gene Caring Cessation of life Chemokine Receptor Gene Chemotaxis Clinical Coronary Arteriosclerosis Coronary heart disease Cutaneous DMA-methyltransferase DNA DNA Methyltransferase DNA Modification Methylases Data Defect Development Disease Disease susceptibility Elderly Event Flow Cytometry Galactosidase Gene Expression Gene Expression Regulation Genes Genetic Transcription Goals Granulocyte-Macrophage Colony-Stimulating Factor High Prevalence Human Immune In Vitro Incidence Inflammation Inflammation Mediators Inflammatory Inflammatory Response Interleukin-2 Knockout Mice Lead Leukocytes Longevity Luciferases Measures Mediating Memory Methylation Modeling Molecular Mus Outcome Pathogenesis Patients Play Population Process Proteins Public Health RNA RNA Degradation Reaction Regulation Reporter Reporting Request for Applications Research Design Research Personnel Ribonucleases Role System T-Lymphocyte T-Lymphocyte Subsets Testing Transfection Western Blotting Writing age effect age related aged beta-Chemokines bisulfite chemokine chemokine receptor cytokine design improved in vitro testing in vivo knockout animal middle age monocyte mouse model novel older patient overexpression patient population programs promoter protein expression receptor expression receptor function research study response senescence transcription factor

项目摘要

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）：已知的与年龄相关的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与年龄相关的炎症介质变化是否独立于与年龄相关的疾病而发生，或者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已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，衰老与特定 CC 趋化因子受体（包括 CCR2 和 CCR5）基因表达的增加有关。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以下假设：衰老与白细胞 C-C 趋化因子受体表达增加有关，而白细胞 C-C 趋化因子受体表达增加是由年龄相关的 C-C 趋化因子受体启动子甲基化引起的，由此导致的白细胞趋化因子受体表达增加反过来又有助于老年人冠心病患病率较高。具体目标 1 将定义正常人类衰老和患有冠状动脉疾病的老年人中 T 细胞和单核细胞趋化因子受体的表达和功能，包括基因（微阵列、核糖核酸酶保护测定）、蛋白质（蛋白质印迹、流式细胞术）和功能（趋化性）化验）水平。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确定启动子甲基化在衰老冠状动脉疾病中白细胞趋化因子受体 (CCR1、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，确定趋化因子受体缺陷和 DNA 低甲基化对衰老过程中动脉粥样硬化体内进展的影响。与公共卫生的相关性：65 岁以上的患者虽然仅占美国人口的 13%，但占所有急性心肌梗塞 (MI) 的 60% 以上和所有 M1 死亡的 85% 以上。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，并可能为迅速老龄化的美国人口带来新的治疗方法。