The BB rat is a perfect model for organ specific autoimmune disease. Insulin and insulin-dependent diabetes mellitus (IDDM) and thyroiditis develop in a manner similar to humans. We demonstrate that the development of IDDM and thyroiditis is governed by three genetic factors. We have used marker assisted genotyping for introgression of the diabetes prone (DP) lymphopenia (lyp) locus (iddm1) on chromosome 4 onto our own inbred line of diabetes resistant (DR) BB rats which we have kept in sister-brother breeding since 1982. All rats homozygous for iddml (lyp/lyp) develop insulitis and diabetes. Heterozygous (lyp/+) and wild type (+1+) are diabetes resistant. In crosses between our lyp/lyp BB DR rats and inbred Lewis and Fischer rats, respectively, we have successfully determined the chromosomal location of all three genes: iddm1 (lyp) on chromosome 4, iddm2 (MHC RT1.B) on chromosome 20 and iddm3 on chromosome 2.
The Specific aims are: (1) Determine lyp gene expression and autoreactivity in iddml congenic BB DR rats: (2) Determine lyp gene expression and autoreactivity in iddml congenic Fischer rats; (3) Determine iddm3 gene expression and autoreactivity in iddm3 congenic lyp/lyp BB DR rats. In collaboration with Project 3 we will (1) complete the introgression of the lyp locus (iddm1) onto the BB diabetes resistant (DR) inbred rat by cyclic cross-intercross breeding using marker assisted selection and a total genome scan, (2) establish introgression of iddml onto inbred F344 Fischer rats and (3) establish introgression of the Fischer iddm3 locus onto the lyp/lyp BB DR rat, both by marker assisted selection using the Speed Congenic Strategy. In collaboration with Project 2 we will clone the lyp gene by position with the major aim of this project to identify by in situ hybridization the detailed phenotyping and microstructure of lyp gene expression and analyze the linkage between lyp and autoantigen-specific T cello by quantitative cytospot in situ hybridization and immunospot assay of cytokine secretion. In collaboration with Project 3 we will clone the iddm3 gene by position and identify by in situ hybridization which cell express the iddm3 gene and determine the iddm3 phenotype. The long-term objective of this research is to characterize the iddm1, iddm2 and iddm3 genes and determine the mechanisms by which three genes interact to induce insulitis and IDDM as well as thyroiditis. This research should help us to understand the general mechanisms of autoimmune diseases.
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