Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) that afflicts millions of young adults worldwide. Although the etiology is not known, the pathogenesis of MS appears to involve the breakdown of immune self-tolerance leading to inflammatory demyelinating attack on the CNS. Activation of macrophage/microglia, secretion of IL-12, differentiation of encephalitogenic Th1 cells and secretion of IFN gamma is critical events in CNS demyelination. Increased levels of IL-12 in the CNS associate with clinical disease in human and EAE animal model of MS. Inhibition of IL-12/IFN gamma axis prevents the development of EAE. Targeted expression of IL-12 in the CNS resulted spontaneous inflammation and demyelination in GF-IL-12 transgenic mice. PPAR gamma is a nuclear hormone receptor that regulates immune cell activation and inflammation. PPAR gamma agonists have been used for the treatment of diabetes and inflammatory diseases. Our preliminary studies suggested that PPAR gamma regulates IL-12/IFN gamma axis and CNS inflammation and demyelination in SJL/J mice. In this project, we propose to investigate the molecular mechanisms in PPAR gamma regulation of IL 12/IFN gamma axis in CNS demyelination. Using PPAR gamma agonists, 15d-PGJ2 and Ciglitazone, we will define the mechanisms in the PPAR gamma regulation of JAK-STAT and NF-kB signaling pathways leading to IL-12 gene expression in microglia and IFN gamma secretion in cells. Using GF-IL-12 transgenic mice we will define the mechanisms in the PPAR gamma regulation of IL-12 signaling leading to IFN gamma gene expression and Th1 differentiation in vitro and in vivo. Using GF-IL-12 transgenic and PPAR gamma heterozygous mice, we will define the role of PPAR gamma in the regulation of IL-12/IFN gamma axis in the pathogenesis of CNS inflammation and demyelination. We believe that this project is novel and will provide new insights on the mechanisms of PPAR gamma regulation of signaling pathways in IL-12/IFN gamma axis in Th1 differentiation in vitro and in CNS demyelination in vivo and new therapeutic agents for the treatment of human MS and other inflammatory autoimmune demyelinating diseases of the CNS. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS042257-01A2
Application #
6580502
Study Section
Special Emphasis Panel (ZRG1-BDCN-4 (01))
Program Officer
Utz, Ursula
Project Start
2002-12-15
Project End
2005-11-30
Budget Start
2002-12-15
Budget End
2003-11-30
Support Year
1
Fiscal Year
2003
Total Cost
$209,475
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Neurology
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Chearwae, Wanida; Bright, John J (2008) 15-deoxy-Delta(12,14)-prostaglandin J(2) and curcumin modulate the expression of toll-like receptors 4 and 9 in autoimmune T lymphocyte. J Clin Immunol 28:558-70
Mo, Caiqing; Chearwae, Wanida; O'Malley, John T et al. (2008) Stat4 isoforms differentially regulate inflammation and demyelination in experimental allergic encephalomyelitis. J Immunol 181:5681-90
Rajasingh, Johnson; Bright, John J (2006) 15-Deoxy-delta12,14-prostaglandin J2 regulates leukemia inhibitory factor signaling through JAK-STAT pathway in mouse embryonic stem cells. Exp Cell Res 312:2538-46
Muthian, Gladson; Raikwar, Himanshu P; Rajasingh, Johnson et al. (2006) 1,25 Dihydroxyvitamin-D3 modulates JAK-STAT pathway in IL-12/IFNgamma axis leading to Th1 response in experimental allergic encephalomyelitis. J Neurosci Res 83:1299-309
Rajasingh, Johnson; Raikwar, Himanshu P; Muthian, Gladson et al. (2006) Curcumin induces growth-arrest and apoptosis in association with the inhibition of constitutively active JAK-STAT pathway in T cell leukemia. Biochem Biophys Res Commun 340:359-68
Raikwar, Himanshu P; Muthian, Gladson; Rajasingh, Johnson et al. (2006) PPARgamma antagonists reverse the inhibition of neural antigen-specific Th1 response and experimental allergic encephalomyelitis by Ciglitazone and 15-deoxy-Delta12,14-prostaglandin J2. J Neuroimmunol 178:76-86
Muthian, Gladson; Pradeep, Chellappan G; Sargapradeep, Kuttappan et al. (2006) Setaria digitata secreted filarial lipids modulate IL-12 signaling through JAK-STAT pathway leading to the development of Th1 response. Exp Parasitol 114:193-203
Muthian, Gladson; Raikwar, Himanshu P; Johnson, Caroline et al. (2006) COX-2 inhibitors modulate IL-12 signaling through JAK-STAT pathway leading to Th1 response in experimental allergic encephalomyelitis. J Clin Immunol 26:73-85
Raikwar, Himanshu P; Muthian, Gladson; Rajasingh, Johnson et al. (2005) PPARgamma antagonists exacerbate neural antigen-specific Th1 response and experimental allergic encephalomyelitis. J Neuroimmunol 167:99-107
Bright, John J (2004) Targeting autoimmune diseases through nutraceuticals. Nutrition 20:39-43

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