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. ? ? ? ? ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG028268-02
Application #
7282472
Study Section
Special Emphasis Panel (ZAG1-ZIJ-5 (M1))
Program Officer
Fuldner, Rebecca A
Project Start
2006-09-01
Project End
2011-06-30
Budget Start
2007-07-01
Budget End
2008-06-30
Support Year
2
Fiscal Year
2007
Total Cost
$324,154
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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Ghosh, Amiya Kumar; Mau, Theresa; O'Brien, Martin et al. (2018) Novel role of autophagy-associated Pik3c3 gene in gonadal white adipose tissue browning in aged C57/Bl6 male mice. Aging (Albany NY) 10:764-774
Julius, Annabelle; Desai, Anjali; Yung, Raymond L (2017) Recombinant human erythropoietin stimulates melanoma tumor growth through activation of initiation factor eIF4E. Oncotarget 8:30317-30327
Ghosh, Amiya Kumar; Mau, Theresa; O'Brien, Martin et al. (2016) Impaired autophagy activity is linked to elevated ER-stress and inflammation in aging adipose tissue. Aging (Albany NY) 8:2525-2537
Delaney, Colin; Garg, Sanjay K; Yung, Raymond (2015) Analysis of DNA Methylation by Pyrosequencing. Methods Mol Biol 1343:249-64
Ghosh, Amiya Kumar; Garg, Sanjay Kumar; Mau, Theresa et al. (2015) Elevated Endoplasmic Reticulum Stress Response Contributes to Adipose Tissue Inflammation in Aging. J Gerontol A Biol Sci Med Sci 70:1320-9
Garg, Sanjay K; Delaney, Colin; Toubai, Tomomi et al. (2014) Aging is associated with increased regulatory T-cell function. Aging Cell 13:441-8
Garg, Sanjay K; Delaney, Colin; Shi, Hang et al. (2014) Changes in adipose tissue macrophages and T cells during aging. Crit Rev Immunol 34:1-14
Strickland, Faith M; Hewagama, Anura; Wu, Ailing et al. (2013) Diet influences expression of autoimmune-associated genes and disease severity by epigenetic mechanisms in a transgenic mouse model of lupus. Arthritis Rheum 65:1872-81
Delaney, Colin; Garg, Sanjay K; Fernandes, Chris et al. (2013) Maternal diet supplemented with methyl-donors protects against atherosclerosis in F1 ApoE(-/-) mice. PLoS One 8:e56253

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