GENETICS AND PATHOLOGY OF NON-OBESE DIABETIC (NOD) MICE

Summary

Principal Investigator: Edward Leiter
Affiliation: The Jackson Laboratory
Country: USA
Abstract: The long term goal of this project is identification of the chromosomal locations and functions of genes controlling diabetes pathogenesis in NOD/Lt mice. Insulin dependent diabetes in NOD/Lt mice is under polygenic control and reflects development of a dysregulated immune system in which autoreactive T cells are neither deleted intrathymically nor suppressed peripherally. Genes within the major histocompatibility complex (MHC) are important components of the genetic susceptibility; however, non-MHC susceptibility genes interact with the diabetogenic MHC loci to initiate diabetes pathogenesis. Genetic analysis will be centered on NOR/Lt, a NOD- related, diabetes-free stock. This stock contains NOD alleles at MHC and most other non-MHC loci typed, but contains segments of 4 chromosomes derived from the C57BL/KsJ strain. Diabetes resistance in the NOR stock is accompanied by a reconstituted syngeneic mixed lymphocyte reaction (SMLR), a peripheral T cell response absent in NOD/Lt. Thus, presence or absence of SMLR activity serves as a valuable immunophenotypic marker to segregate analysis the C57BL/KsJ genes in NOR/Lt abrogating diabetes pathogenesis and relate them to immunophenotypic markers. This will be accomplished by development of NOD stocks congenic for chromosomal segments carrying diabetes resistance alleles from NOR. The second aim is to analyze by genetic segregation how pathogenesis-predisposing MHC haplotypes interact with diabetogenic non-MHC genes (defined in the first aim) to mediate pathogenesis via perturbation of immunoregulatory systems. The third aim is to develop monoclonal antibodies to permit characterization of Mrt-6, a mouse gene we mapped to Chr 7 and homologous to RT6 in the rat. RT6 is a T cell surface differentiation antigen defined in rats; a subset of RT6+ T cells possess immunoregulatory function since their depletion elicits diabetes in heretofore resistant rats. Northern blot analysis reveals lower Mrt-6 RNA expression in NOD compared to diabetes-resistant mice, indicating that Mrt-6 may also serve as a marker for immunoregulatory subsets in the NOD mouse. The fourth aim is to investigate the potential pathogenic significance of pancreatic beta cell expression of an endogenous ecoptropic proviral gene, Emy-30, located on Chr 11 of NOD and absent in the diabetes resistant NOR stock. We will establish the molecular basis for differential expression of this endogenous retrovirus in NOD beta cells versus beta cells from related but diabetes-resistant stocks. Results from these proposed studies will guide geneticists in their search for non-MHC linked diabetogenic susceptibility genes in humans and enhance understanding of their interactions with diabetogenic MHC genes.
Funding Period: 1985-07-01 - 1995-06-30
more information: NIH RePORT

Top Publications

  1. ncbi mt-Nd2 Allele of the ALR/Lt mouse confers resistance against both chemically induced and autoimmune diabetes
    C E Mathews
    Department of Pediatrics, Diabetes Institute, Children s Hospital of Pittsburgh, University of Pittsburgh School of Medicine, 3460 5th Ave, Rangos Research Center, Pittsburgh, PA 15213, USA
    Diabetologia 48:261-7. 2005
  2. pmc Commonalities of genetic resistance to spontaneous autoimmune and free radical--mediated diabetes
    Jing Chen
    Department of Pediatrics, The University of Pittsburgh School of Medicine, Pittsburgh, PA 15213 USA
    Free Radic Biol Med 45:1263-70. 2008
  3. ncbi Unexpected functional consequences of xenogeneic transgene expression in beta-cells of NOD mice
    E H Leiter
    The Jackson Laboratory, Bar Harbor, ME 04609, USA
    Diabetes Obes Metab 9:14-22. 2007
  4. ncbi CD38 is required for the peripheral survival of immunotolerogenic CD4+ invariant NK T cells in nonobese diabetic mice
    Yi Guang Chen
    The Jackson Laboratory, Bar Harbor, ME 04609, USA
    J Immunol 177:2939-47. 2006
  5. ncbi Targeted disruption of CD38 accelerates autoimmune diabetes in NOD/Lt mice by enhancing autoimmunity in an ADP-ribosyltransferase 2-dependent fashion
    Jing Chen
    The Jackson Laboratory, Bar Harbor, ME 04609, USA
    J Immunol 176:4590-9. 2006
  6. ncbi Novel leptin receptor mutation in NOD/LtJ mice suppresses type 1 diabetes progression: II. Immunologic analysis
    Chul Ho Lee
    The Jackson Laboratory, 600 Main St, Bar Harbor, ME 04609, USA
    Diabetes 55:171-8. 2006
  7. ncbi Mouse models and the genetics of diabetes: is there evidence for genetic overlap between type 1 and type 2 diabetes?
    Edward H Leiter
    The Jackson Laboratory, 600 Main St, Bar Harbor, Maine 04609, USA
    Diabetes 54:S151-8. 2005
  8. ncbi "Agouti NOD": identification of a CBA-derived Idd locus on Chromosome 7 and its use for chimera production with NOD embryonic stem cells
    Jing Chen
    The Jackson Laboratory, 600 Main Street, Bar Harbor, Maine 04609 1500, USA
    Mamm Genome 16:775-83. 2005
  9. ncbi Novel leptin receptor mutation in NOD/LtJ mice suppresses type 1 diabetes progression: I. Pathophysiological analysis
    Chul Ho Lee
    The Jackson Laboratory, 600 Main St, Bar Harbor, ME 04609, USA
    Diabetes 54:2525-32. 2005
  10. ncbi Conditioning the genome identifies additional diabetes resistance loci in Type I diabetes resistant NOR/Lt mice
    P C Reifsnyder
    The Jackson Laboratory, Bar Harbor, ME 04609, USA
    Genes Immun 6:528-38. 2005

Scientific Experts

  • Edward Leiter
  • C E Mathews
  • Jing Chen
  • Chul Ho Lee
  • Yi Guang Chen
  • David V Serreze
  • Peter C Reifsnyder
  • Friedrich Koch-Nolte
  • Peter Reifsnyder
  • Mark A Atkinson
  • William H Schott
  • Felix Scheuplein
  • Clive Wasserfall
  • Friedrich Haag
  • Christian Krebs
  • P C Reifsnyder
  • Darcy P Pomerleau
  • Renhua Li
  • Brian W Soper
  • Ying Lu
  • Mark D Lessard
  • William Schott
  • Darcy Pomerleau
  • Steven A Porcelli
  • S Brian Wilson
  • Melissa Osborne
  • Gurdyal S Besra
  • Michelle Rodriguez
  • Melissa A Osborne
  • Harold D Chapman
  • Michael Clare-Salzler
  • Michel Seman
  • Andras Nagy
  • G Churchill
  • Rebecca J Bagley
  • James Ellis
  • P A Silveira
  • Fenja Braasch
  • Sharon Soodeen-Karamath
  • Jurgen K Naggert
  • Frances E Lund
  • Maria Mileikovsky
  • Norman Oppenheimer
  • Wolfgang Koestner
  • D V Serreze
  • R Li
  • Sahil Adriouch
  • Michael H Dosch

Detail Information

Publications15

  1. ncbi mt-Nd2 Allele of the ALR/Lt mouse confers resistance against both chemically induced and autoimmune diabetes
    C E Mathews
    Department of Pediatrics, Diabetes Institute, Children s Hospital of Pittsburgh, University of Pittsburgh School of Medicine, 3460 5th Ave, Rangos Research Center, Pittsburgh, PA 15213, USA
    Diabetologia 48:261-7. 2005
    ..Here we show that the mitochondrial genome (mtDNA) of ALR mice contributes resistance to diabetes...
  2. pmc Commonalities of genetic resistance to spontaneous autoimmune and free radical--mediated diabetes
    Jing Chen
    Department of Pediatrics, The University of Pittsburgh School of Medicine, Pittsburgh, PA 15213 USA
    Free Radic Biol Med 45:1263-70. 2008
    ..mt(NOD) mice, whereas it was decreased by congenic introduction of ALR genome on Chr. 8 into NOD. These data demonstrate both similarities and differences in the genetic control of T1D versus ROS-induced diabetes...
  3. ncbi Unexpected functional consequences of xenogeneic transgene expression in beta-cells of NOD mice
    E H Leiter
    The Jackson Laboratory, Bar Harbor, ME 04609, USA
    Diabetes Obes Metab 9:14-22. 2007
    ..These findings emphasize the need for careful characterization of genetically manipulated NOD mouse stocks to insure that model characteristics have not been compromised...
  4. ncbi CD38 is required for the peripheral survival of immunotolerogenic CD4+ invariant NK T cells in nonobese diabetic mice
    Yi Guang Chen
    The Jackson Laboratory, Bar Harbor, ME 04609, USA
    J Immunol 177:2939-47. 2006
    ..Therefore, this study documents a previously unrecognized role for CD38 in maintaining survival of an iNKT cell subset that preferentially contributes to the maintenance of immunological tolerance...
  5. ncbi Targeted disruption of CD38 accelerates autoimmune diabetes in NOD/Lt mice by enhancing autoimmunity in an ADP-ribosyltransferase 2-dependent fashion
    Jing Chen
    The Jackson Laboratory, Bar Harbor, ME 04609, USA
    J Immunol 176:4590-9. 2006
    ..Unexpectedly, diabetes development in the combined CD38/ART2 stock was strongly suppressed, possibly through epistatic interactions between genes linked to the targeted CD38 on Chromosome 5 and the ART2 complex on Chromosome 7...
  6. ncbi Novel leptin receptor mutation in NOD/LtJ mice suppresses type 1 diabetes progression: II. Immunologic analysis
    Chul Ho Lee
    The Jackson Laboratory, 600 Main St, Bar Harbor, ME 04609, USA
    Diabetes 55:171-8. 2006
    ....
  7. ncbi Mouse models and the genetics of diabetes: is there evidence for genetic overlap between type 1 and type 2 diabetes?
    Edward H Leiter
    The Jackson Laboratory, 600 Main St, Bar Harbor, Maine 04609, USA
    Diabetes 54:S151-8. 2005
    ..The conclusion is that although overlap exists in the pathophysiological insults leading to beta-cell destruction in the currently studied rodent models, the genetic bases seem quite distinct...
  8. ncbi "Agouti NOD": identification of a CBA-derived Idd locus on Chromosome 7 and its use for chimera production with NOD embryonic stem cells
    Jing Chen
    The Jackson Laboratory, 600 Main Street, Bar Harbor, Maine 04609 1500, USA
    Mamm Genome 16:775-83. 2005
    ..CBALs- Tyr(+)/Lt blastocysts produced approximately 50% live-born mice, of which approximately 11% were chimeric. Presumably because of high genomic instability, no germline transmission was observed...
  9. ncbi Novel leptin receptor mutation in NOD/LtJ mice suppresses type 1 diabetes progression: I. Pathophysiological analysis
    Chul Ho Lee
    The Jackson Laboratory, 600 Main St, Bar Harbor, ME 04609, USA
    Diabetes 54:2525-32. 2005
    ....
  10. ncbi Conditioning the genome identifies additional diabetes resistance loci in Type I diabetes resistant NOR/Lt mice
    P C Reifsnyder
    The Jackson Laboratory, Bar Harbor, ME 04609, USA
    Genes Immun 6:528-38. 2005
    ..11. These findings emphasize the value for diabetes gene discovery of stratifying not only MHC loci conferring the highest relative risk but also as many as possible of the non-MHC loci presumed to contribute significantly...
  11. ncbi Mechanisms underlying resistance of pancreatic islets from ALR/Lt mice to cytokine-induced destruction
    Clayton E Mathews
    Diabetes Institute, Children s Hospital of Pittsburgh, University of Pittsburgh School of Medicine, 3460 5th Avenue, Pittsburgh, PA 15221, USA
    J Immunol 175:1248-56. 2005
    ....
  12. ncbi Major histocompatibility complex-linked diabetes susceptibility in NOD/Lt mice: subcongenic analysis localizes a component of Idd16 at the H2-D end of the diabetogenic H2(g7) complex
    Darcy P Pomerleau
    The Jackson Laboratory, 600 Main St, Bar Harbor, ME 04609, USA
    Diabetes 54:1603-6. 2005
    ..33 mB, distinguishing D.R2 from D.R3. Evidence supporting the candidacy of the ALR/CTS-shared H2-D(dx) MHC class I variant present in both diabetes-resistant stocks, but not the susceptible stock, is discussed...
  13. ncbi Nonobese diabetic mice and the genetics of diabetes susceptibility
    Edward H Leiter
    The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609, USA
    Curr Diab Rep 5:141-8. 2005
    ..An understanding of how variable collections of genes interact with each other and with environmental cues offers important insights as to the complexities of T1D inheritance in humans...
  14. ncbi CD38 controls ADP-ribosyltransferase-2-catalyzed ADP-ribosylation of T cell surface proteins
    Christian Krebs
    Institute of Immunology, University Hospital, Hamburg, Germany
    J Immunol 174:3298-305. 2005
    ....
  15. ncbi Bone marrow expressing a diabetes resistance MHC class II allele: diabetes deviation by chronic immune stimulation
    Peter Reifsnyder
    The Jackson Laboratory, Bar Harbor, ME 04609, USA
    Novartis Found Symp 292:32-46; discussion 46-9, 122-9, 202-3. 2008
    ....