Lipids play a fundamental role in many of the major diseases (atherosclerosis, cancer, arthritis) in the elderly as well as in aging itself. Specifically, phosphatidic acid (PA) plays a central role in cell function by modifying membrane structure via synthesis into phospholipids and serving as a potent intracellular signaling molecule. Recently, the intracellular lipid binding protein, acyl-CoA binding protein (ACBP), has emerged as an important regulator of PA synthesis and intracellular signaling. Phospholipid alterations in T-cells are associated with reduced immune function in the elderly. Problem: Aging results in significant changes in phospholipid mass and fatty acid composition in T-cells, however, the biochemical and molecular mechanism(s) causing these alterations is not known. Purpose: 1) Determine if reduced PA biosynthesis via glycerol-3-phosphate acyltransferase (GPAT) accounts, at least in part, for reduced T-cell proliferation; 2) Determine the role of ACBP in PA biosynthesis in aged T-cell dysfunction; 3) Assess the role of ACBP in aged T-cell subset dysfunction. Methods: Young and old rats fed ad libitum diets will bell used. Endoplasmic reticulum (ER) (microsomes) and mitochondria will be isolated from the splenic T-cells because the ER and mitochondria are the major sites of de novo PA biosynthesis. The work will focus on the acylation of glycerol-3-phosphate to lysophosphatidic acid then to PA by (GPAT) and lysophosphatidic acid acyltransfcrase respectively. Experiments will be designed to determine if the aging effects on GPAT are pre- (gene expression) or posttranscriptional (phosphorylation, protein levels) in nature. This is significant because GPAT is the rate-limiting enzyme in PA biosynthesis. The influence of ACBP in mediating reduced T-cell function with age will be assessed by examining whether over-expressed ACBP alters T-cell oroliferation and what impact aging has on ACBP levels by analyzing protein and gene expression by western immunoblotting_and RT-PCR, respectively. ACBP's influence on CD4+ and CD8+ T-cell sub sets and memory/naive-T-cell function with age will be determined by transfecting ACBP into those aged T-cell populations which exhibit altered ACBP expression with age and examining cytokine production by flow cytometry. Outcome: The experiments will give insight into whether alterations in PA synthesis and ACBP expression or function are an important mechanistic explanation for the age-dependent loss of T-cell proliferation. Secondly, insight will be gained into whether ACBP plays a role in the age-dependent dysfunction of specific T-cell subsets. Benefit: Characterizing the influence of aging on ACBP and PA synthesis may ultimately lead to the development of dietary and/or pharmacologic strategies aimed at maintaining optimal immune function hence improving the quality of life in the elderly.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG020651-02
Application #
6664951
Study Section
Special Emphasis Panel (ZRG1-GRM (01))
Program Officer
Fuldner, Rebecca A
Project Start
2002-09-15
Project End
2007-07-31
Budget Start
2003-08-15
Budget End
2004-07-31
Support Year
2
Fiscal Year
2003
Total Cost
$223,000
Indirect Cost
Name
University of Texas Austin
Department
Social Sciences
Type
Schools of Arts and Sciences
DUNS #
170230239
City
Austin
State
TX
Country
United States
Zip Code
78712
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