Identification of genes involved in the pathogenesis and predictive markers for type 1 diabetes in NOD mice (She, Muir,Clare-Salzler, McIndoe & Wang):


This is the continuation of our ongoing research effort on the NOD mouse model for type 1 diabetes. We will profile gene expression in the spleen and pancreatic lymph nodes at 3 different time points and various mouse strains. These strains include NOD, normal controls (B6, Balb/C, SWR), an autoimmune lupus model (NZW2410), NOD-related strains (NON & NOR) and NOD congenic strains containing B6 or B10-derived Idd intervals (NOD.B6Idd3, NOD.B10Idd5 and double congenic strain NOD.B6Idd3B10Idd5). NON and NOR share about 80% of the NOD genome but do not develop diabetes. The congenic mice have reduced incidence for diabetes and insulitis. The double congenic mice are especially useful because less than 5% of them develop diabetes and <20% develop insulitis. The mouse strains are carefully selected in order to maximize our ability to distinguish diabetes-relevant expression difference from strain variation. We will focus on those genes that differ between NOD and all control strains because they are more likely disease-relevant. It is also interesting to distinguish primary changes (due to mutation within the genes) and secondary changes (due to primary genes or the disease process). The comparison between NOD and NOD-related strains and the NOD congenic strains should be very helpful for this purpose. The double congenic strain is of particular importance because most differences between NOD and the double congenic should be due to the disease process as their genomes are identical except 2 diabetes protective intervals derived from B6 or B10. The inclusion of the NZW2410 lupus model will allow us to distinguish genes important for diabetes or the autoimmune process in general. The study time points for each tissue (4wks, 10wks and diabetic) are also carefully considered to maximize useful information and minimize cost. Other time points may be considered. We choose the first time point because the earliest starting point of insulitis for NOD is 5wks in our colony. At 10wks, lymphocyte infiltration is very severe in most NOD mice. The last time point is immediately after onset of clinical diabetes, usually between 15-20wks. These studies should allow us to identify a number of candidate genes involved in autoimmunity and/or diabetes as well as molecular markers associated with disease progression. The combination of microarray and congenic approaches should provide a very powerful tool to dissect the genetic pathways of complex diseases. These approaches have already been proven successful in our preliminary studies. Once the candidate genes are identified, our comprehensive research program will allow us to determine the full length cDNA sequence and functional characterization of the proteins using a number of approaches that are being estabilshed in our group. More importantly, we will be able to compare our mouse data with the human studies described in project 3.
 

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