Many epidemiological and clinical studies have demonstrated that n-3 polyunsaturated fatty acids (PUPA), a bioactive food component, ameliorate immune-mediated inflammatory diseases. A primary effector molecule is thought to be docosahexaenoic acid (DHA, 22:6n-3). However, the precise mechanisms by which DHA influences the maintenance of appropriate T-cell subset balance for a healthy immune system have not been elucidated. Therefore, the overall goal of this proposal is to understand, at a mechanistic level, how dietary DHA modulates T-cell activation and signaling. Our overall hypothesis is that DHA disrupts plasma membrane lipid raft microdomain composition, thereby altering the dynamic partitioning of signaling proteins required for cell proliferation and apoptosis in T-cells. This would selectively alter T-cell receptor (TCR) macromolecular complex signaling, inhibiting activation and cytokine production by T-helper 1 (Th1) cells and/or create a permissive environment for apoptosis in Th1 cells. We will also test the alternative hypothesis that DHA selectively inhibits signaling protein (Lck, Fyn, and LAT) post-translational lipidation, which subsequently may alter lipid raft targeting and protein function. We propose to utilize conventional C57BL/6, IL-10 null, DO11.10-RAG null, and Fat-1 transgenic mouse models to further elucidate the mechanisms by which DHA suppresses Th1-mediated immune responses. The proposed experiments will further elucidate the mechanisms by which DHA: 1) Differentially modulates membrane properties and TCR-dependent signaling in nonpolarized vs Th1 polarized cells; 2) Alters the plasma membrane microenvironment and modulates the function of the major co-regulatory signaling molecules which regulates T-cell proliferation and apoptosis; 3) Directly affects antigen-induced CD4+ T-cell activation and indirectly affects the co-stimulatory environment in vivo; and 4) Suppresses the development of Th1-mediated inflammatory bowel disease in a murine model. Findings from the proposed studies could lead to the development of new therapeutic tools to treat T-cell-mediated inflammation and autoimmunity. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK071707-02
Application #
7354833
Study Section
Integrative Nutrition and Metabolic Processes Study Section (INMP)
Program Officer
May, Michael K
Project Start
2007-02-15
Project End
2012-01-31
Budget Start
2008-02-01
Budget End
2009-01-31
Support Year
2
Fiscal Year
2008
Total Cost
$289,081
Indirect Cost
Name
Texas A&M University
Department
Veterinary Sciences
Type
Schools of Earth Sciences/Natur
DUNS #
078592789
City
College Station
State
TX
Country
United States
Zip Code
77845
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Monk, Jennifer M; Hou, Tim Y; Turk, Harmony F et al. (2012) Dietary n-3 polyunsaturated fatty acids (PUFA) decrease obesity-associated Th17 cell-mediated inflammation during colitis. PLoS One 7:e49739
Monk, Jennifer M; Jia, Qian; Callaway, Evelyn et al. (2012) Th17 cell accumulation is decreased during chronic experimental colitis by (n-3) PUFA in Fat-1 mice. J Nutr 142:117-24
Shaikh, Saame Raza; Jolly, Christopher A; Chapkin, Robert S (2012) n-3 Polyunsaturated fatty acids exert immunomodulatory effects on lymphocytes by targeting plasma membrane molecular organization. Mol Aspects Med 33:46-54
Jia, Qian; Ivanov, Ivan; Zlatev, Zlatomir Z et al. (2011) Dietary fish oil and curcumin combine to modulate colonic cytokinetics and gene expression in dextran sodium sulphate-treated mice. Br J Nutr 106:519-29
Monk, Jennifer M; Hou, Tim Y; Chapkin, Robert S (2011) Recent advances in the field of nutritional immunology. Expert Rev Clin Immunol 7:747-9
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Chapkin, Robert S; Zhao, Chen; Ivanov, Ivan et al. (2010) Noninvasive stool-based detection of infant gastrointestinal development using gene expression profiles from exfoliated epithelial cells. Am J Physiol Gastrointest Liver Physiol 298:G582-9

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