Chemokine biology has emerged as central to many important immune and inflammatory processes. However, very little is known about the effect of aging on T cell chemokine function. The specific goal of this proposal is to test the hypothesis that aging is associated with increased T cell C-C chemokine receptor expression that is caused by C-C chemokine receptor promoter hypomethylation.
Specific Aim 1 will test the first part of the hypothesis that aging is associated with increased T cell C-C chemokine receptor expression. The effects of aging on T cell C-C and C-X-C chemokine receptor expression and function will be defined at 1. The RNA level (screening by microarray GeneChip technology and confirmed by ribonuclease protection assays (RPAs)). 2. The protein level (Western blot). 3. The functional level (in vitro adhesion and chemotactic assays and in vivo murine chemokine-dependent cutaneous inflammation model). In addition, T cell chemokine response following cytokine stimulation will be determined.
Specific Aim 2 will test the second half of the hypothesis that promoter hypomethylation is the mechanism responsible for aging-associated increased in T cell C-C chemokine receptor gene expression. Regulation of CCR5 gene at the transcriptional level will be confirmed by RNA degradation studies and In vitro transcription nuclear run-on assay. The role of transcription factors in the regulation of CCR5 gene expression will be excluded by transfection studies using promoter constructs and the luciferase/beta- galactosidase reporter system. Bisulfite sequencing will be done to determine the promoter methylation status of T cells from across the life span. """"""""Patch"""""""" methylation of the CCR5 promoter will be done to determine the effect of DNA methylation. Finally, expression of DNA methyltransferases and the related regulatory proteins will be determined by RPAs and Western blots.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG020628-03
Application #
6942591
Study Section
Geriatrics and Rehabilitation Medicine (GRM)
Program Officer
Fuldner, Rebecca A
Project Start
2003-08-01
Project End
2008-07-31
Budget Start
2005-08-15
Budget End
2006-07-31
Support Year
3
Fiscal Year
2005
Total Cost
$343,733
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
Mau, Theresa; Yung, Raymond (2018) Adipose tissue inflammation in aging. Exp Gerontol 105:27-31
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
Figueroa-Romero, Claudia; Hur, Junguk; Lunn, J Simon et al. (2016) Expression of microRNAs in human post-mortem amyotrophic lateral sclerosis spinal cords provides insight into disease mechanisms. Mol Cell Neurosci 71:34-45
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

Showing the most recent 10 out of 23 publications