Genetic and molecular analysis of the insulin dependent diabetes 4 locus in the NOD mouse.
Published: 2004
Language: eng
Number of pages: 228
Description: Type 1 diabetes (T1D) is a disorder in which pancreatic beta cells are destroyed by autoimmune attack. The NOD mouse recapitulates many steps in the pathogenesis of the human disease. More than 20 Idd loci have been linked to T1D susceptibility in the NOD model and, of these, only three are defined at the gene level. Progressive islet infiltration (insulitis) results in T1D in 85% of NOD females but only 10--40% of NOD males by 6 months of age. Cyclophosphamide (CY) treatment accelerates onset in NOD males and females but not other laboratory strains. My PhD work aimed to identify genetic underpinnings of CY-accelerated T1D in the NOD mouse. First, genetic analysis of the CY response in NOD compared to the genetically related,  Idd1 identical, but T1D-resistant NOR strain was performed. Progression to severe insulitis was linked to Idd4 and Idd9/11 . Idd4, Idd9/11, Idd5 and Idd13 congenic strains were then generated on both genetic backgrounds and examined for CY-T1D. On the NOR background, NOD-derived Idd4 or  Idd9/11 increased T1D susceptibility in both males and females. NOR-derived  Idd4, Idd5 or Idd9/11 intervals conferred protection from CY-T1D in females, but only the NOR Idd5 or  Idd9/11 interval effectively protected males. High-resolution physical mapping of Idd4 confirmed its sex dependent behavior and revealed at least two loci within this region. Both Idd4.1 and Idd4.2 were refined to 1.4 Mb intervals containing 52 and 47 genes, respectively. Idd4.1 displayed its strongest effect in males, whereas Idd4.2 influenced mainly females. Analysis of all candidate genes in the Idd4.1 locus using expression profiling and functional annotation was then performed. Eight genes, including proteasomal subunit Psmb6, were differentially expressed in a tissue-specific manner from strains congenic at this locus. Sequencing of Psmb6 revealed multiple nucleotide variations between NOD and NOR. Coding regions were also sequenced for several immunologically relevant genes that were equally expressed in NOR and NOR.NOD-Idd4 . A putative functional variation in the transmembrane chemokine  Cxcl16 has been identified. Due to the central role of Psmb6  in antigen presentation and Cxcl16 in lymphocyte trafficking, both are excellent candidates for the Idd4.1 locus.
Notes: Adviser: Jayne S. Danska.

Thesis (Ph.D.)--University of Toronto, 2004.

Electronic version licensed for access by U. of T. users.

Source: Dissertation Abstracts International, Volume: 65-10, Section: B, page: 4964.