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.
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