Application of Genetics and Physiological Genomics to Dissect Resistance to T1D

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Type 1 diabetes (T1D) is one of the prototypical organ-specific autoimmune endocrinopathies that results in life-long dependency on daily insulin injection. Molecular genetic approaches have identified regions of the human, mouse, rat genomes that play a role in susceptibility to Type 1 Diabetes (T1D). While the major histocompatibility complex (MHC), the equivalent of the human leukocyte antigen (HLA), is the major locus responsible for susceptibility to T1D, there is a separate set of genes that contribute to susceptibility and end organ damage. We have been studying the genetic factors contributing to T1D in the BBDP rat, a model of spontaneous disease concurrent with lymphopenia. We have identified the location of five loci involved in T1D: Iddm2/lyp, lddm1/MHC, Iddm3, Iddm19, and a fifth locus on chromosome 4 (Iddm4?). Given the identification of the Ian5 mutation as the gene responsible for Iddm2/lyp, we now focus on the identification of the additional factors playing a role in T1D in the BB rat. Our mapping studies have identified four diabetogenic loci in addition to the MHC, which Projects 3 specifically addresses, in close collaboration with Project 1. The focus of Project 3 is to generate consomic and derived congenic strains for three additional factors, including Iddm3, Iddm19, and the susceptibility locus on chromosome 4 nearby Ian5 (Project 1) and to evaluate these new models for their role in T1D using gene expression profiling, comparative genomics, and sequence analysis. Furthermore, we are developing the technology to knock genes out in the rat for validation of positionally cloned genes. Specifically we will: 1. Continue positional cloning efforts for Iddm3 to identify sequence variants contributing to resistance to autoimmune diabetes. 2. Follow up a second resistance factor on chromosome 15. 3. Use novel 70-mer oligonucleotide and cDNA microarray platforms to evaluate genes and pathways affected by the diabetogenic factors identified in the BB rat. 4. Generate rat ENU-induced knockout strains to validate genes involved in autoimmune diabetes in the BB rat.