The non-obese diabetic (NOD) mouse provides an excellent model for e type 1 diabetes mellitus (T1DM). Several lines of evidence suggest that T1DM results from a Th1 autoimmune response. For example, studies by our group and others have shown that islet-reactive Th1 (interferon (IFN)-gamma producing) T cells transfer diabetes, while islet-reactive Th2 (interleukin (IL)-4 producing) T cells do not. These and other data support the notion that T1DM development correlates with a Th1 response. However, the pathogenesis of T1DM, like that of other organ-specific autoimmune diseases, clearly involves more than the development of IFN-gamma producing lymphocytes. Indeed, both IFN-gamma- and IFN-gamma receptor-deficient NOD mice develop T1DM. Therefore, it is critical that a deeper, more mechanistic understanding of the immunopathogenesis of T1DM be established. To this end, we have taken advantage of the spectrum of disease exhibited by sub-lines of our islet-specific T cell receptor (TCR) transgenic NOD mice to analyze the molecular evolution of disease in vivo, using the technique of functional genomics. The general hypotheses underlying these studies are: (a) that diabetes in NOD mice is a Th1-associated disease; (b) that disease expression in the NOD mouse is not dependent upon the expression or activity of IFN-gamma, the superficial phenotype marker of a Th1 response; and (c) that global characterization of disease- and tissue-specific gene expression will allow for a more complete understanding of the pathogenesis of diabetes in the NOD mouse. The specific hypothesis being tested in these studies is that a careful, functional genomics approach to molecular pathogenesis will allow for the detailed delineation of those aspects of the Th1-associated inflammatory response that are truly essential for disease pathogenesis in the NOD mouse. To this end, we aim:
Aim 1 : To establish a limited and verified set of genes whose expression patterns directly stage and predict the course of spontaneous disease progression in NOD mice.
Aim 2 : To delineate the genetic mechanism by which IFN-gamma- and IFN-gamma receptor-deficient NOD mice develop spontaneous T1DM in the absence of interferon-gamma activity.
Aim 3 : To establish the differential gene expression pattern associated with disease progression and resistance in NOD recipients of islet-reactive Th1 and Th2 T cells.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK062274-01
Application #
6535432
Study Section
Immunological Sciences Study Section (IMS)
Program Officer
Akolkar, Beena
Project Start
2002-06-01
Project End
2007-05-31
Budget Start
2002-06-01
Budget End
2003-05-31
Support Year
1
Fiscal Year
2002
Total Cost
$320,050
Indirect Cost
Name
Cincinnati Children's Hospital Medical Center
Department
Type
DUNS #
071284913
City
Cincinnati
State
OH
Country
United States
Zip Code
45229
Sanga, Madhu; Younis, Islam R; Tirumalai, Padma S et al. (2006) Epoxidation of the methamphetamine pyrolysis product, trans-phenylpropene, to trans-phenylpropylene oxide by CYP enzymes and stereoselective glutathione adduct formation. Toxicol Appl Pharmacol 211:148-56
Bland, Tina M; Haining, Robert L; Tracy, Timothy S et al. (2005) CYP2C-catalyzed delta9-tetrahydrocannabinol metabolism: kinetics, pharmacogenetics and interaction with phenytoin. Biochem Pharmacol 70:1096-103
Vukkadapu, Sankaranand S; Belli, Jenine M; Ishii, Koji et al. (2005) Dynamic interaction between T cell-mediated beta-cell damage and beta-cell repair in the run up to autoimmune diabetes of the NOD mouse. Physiol Genomics 21:201-11
Hirani, Vandana N; Raucy, Judy L; Lasker, Jerome M (2004) Conversion of the HIV protease inhibitor nelfinavir to a bioactive metabolite by human liver CYP2C19. Drug Metab Dispos 32:1462-7
Raucy, Judy L (2003) Regulation of CYP3A4 expression in human hepatocytes by pharmaceuticals and natural products. Drug Metab Dispos 31:533-9
Pullinger, Clive R; Eng, Celeste; Salen, Gerald et al. (2002) Human cholesterol 7alpha-hydroxylase (CYP7A1) deficiency has a hypercholesterolemic phenotype. J Clin Invest 110:109-17
Allen, S W; Mueller, L; Williams, S N et al. (2001) The use of a high-volume screening procedure to assess the effects of dietary flavonoids on human cyp1a1 expression. Drug Metab Dispos 29:1074-9
Ross, J A; Radloff, G A; Davies, S M (2000) H19 and IGF-2 allele-specific expression in hepatoblastoma. Br J Cancer 82:753-6
Korzekwa, K R; Krishnamachary, N; Shou, M et al. (1998) Evaluation of atypical cytochrome P450 kinetics with two-substrate models: evidence that multiple substrates can simultaneously bind to cytochrome P450 active sites. Biochemistry 37:4137-47
Pan-Zhou, X R; Cretton-Scott, E; Zhou, X J et al. (1998) Role of human liver P450s and cytochrome b5 in the reductive metabolism of 3'-azido-3'-deoxythymidine (AZT) to 3'-amino-3'-deoxythymidine. Biochem Pharmacol 55:757-66

Showing the most recent 10 out of 38 publications