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Series GSE46600 Query DataSets for GSE46600
Status Public on Jun 20, 2014
Title Transcriptome and Molecular Pathways Analysis of CD4 T-Cells from Young NOD Mice
Organism Mus musculus
Experiment type Expression profiling by array
Summary Type 1 diabetes is a multigenic disease caused by T-cell mediated destruction of the insulin producing β-cells. Although conventional (targeted) approaches of identifying causative genes have advanced our knowledge of this disease, many questions remain unanswered. Using a whole molecular systems study, we unraveled the genes/molecular pathways that are altered in CD4 T-cells from young NOD mice prior to insulitis (lymphocytic infiltration into the pancreas). Many of the CD4 T-cell altered genes lie within known diabetes susceptibility regions (Idd), including several genes in the diabetes resistance region Idd13 and two genes (Khdrbs1 and Ptp4a2) in the CD4 T-cell diabetogenic activity region Idd9/11. Alterations involved apoptosis/cell proliferation and metabolic pathways (predominant at 2 weeks), inflammation and cell signaling/activation (predominant at 3 weeks), and innate and adaptive immune responses (predominant at 4 weeks). We identified several factors that may regulate these abnormalities: IRF-1, HNF4A, TP53, BCL2L1 (lies within Idd13), IFNG, IL4, IL15, and prostaglandin E2, which were common to all 3 ages; AR and IL6 to 2 and 4 weeks; and Interferon (IFN-I) and IRF-7 to 3 and 4 weeks. Others were unique to the various ages (e. g. MYC, JUN, and APP to 2 weeks; TNF, TGFB1, NFKB, ERK, and p38MAPK to 3 weeks; and IL12 and STAT4 to 4 weeks). Our data suggest that diabetes resistance genes in Idd13 and Idd9/11, and BCL2L1, IL6-AR and IFNG-IRF-1-IFN-I/IRF-7-IL12 pathways play an important role in CD4 T-cells in the early pathogenesis of autoimmune diabetes. Thus, the alternative approach of investigation at the molecular systems level has captured new information, which combined with validation studies, offers the opportunity to test hypotheses on the role played by the genes/molecular pathways identified in this study, to understand better the mechanisms of autoimmune diabetes in CD4 T-cells, and to develop new therapeutic strategies for the disease.
 
Overall design CD4 T-cells were purified from spleen leukocytes collected from 2-, 3- and 4-week old NOD mice and two age-matched control strains, NOR, and C57BL/6, (n=5 for each strain and each age group; except NOD2wk). NOR is an insulitis- and diabetes-free control strain that shares shares ~88% of its genome with NOD mice, including the diabetogenic H2g7 MHC haplotype and several important non-MHC T1D susceptibility loci. C57BL/6 is also a diabetes-resitant strain, but it is more genetically distantly related to NOD.
 
Contributor(s) Kakoola DN, Curcio-Brint A, Lenchik NI, Gerling IC
Citation(s) 24918037
Submission date May 02, 2013
Last update date Feb 11, 2019
Contact name Dorothy N. Kakoola
E-mail dkakoola@uthsc.edu
Organization name University of Tennessee Health Science Center
Department Medicine
Lab VA Research
Street address 1030 Jefferson Avenue
City Memphis
State/province TN
ZIP/Postal code 38104
Country USA
 
Platforms (1)
GPL1261 [Mouse430_2] Affymetrix Mouse Genome 430 2.0 Array
Samples (44)
GSM1133080 CD4T-cells_NOD mice_2wk_rep 1
GSM1133081 CD4T-cells_NOD mice_2wk_rep 2
GSM1133082 CD4T-cells_NOD mice_2wk_rep 3
Relations
BioProject PRJNA201061

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Supplementary file Size Download File type/resource
GSE46600_RAW.tar 154.2 Mb (http)(custom) TAR (of CEL)
Raw data provided as supplementary file
Processed data included within Sample table

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