Application of Genetics and Physiological Genomics to Dissect Resistance to T1D

1型糖尿病（T1D）是一种典型的器官特异性自身免疫性内分泌疾病，导致终生依赖每日胰岛素注射。分子遗传学方法已经确定了人类、小鼠和大鼠基因组中与1型糖尿病（T1D）易感性有关的区域。虽然主要组织相容性复合体（MHC），相当于人类白细胞抗原（HLA），是导致T1D易感性的主要基因座，但还有一组单独的基因有助于易感性和终末器官损伤。我们一直在研究导致BBDP大鼠（一种自发性疾病并发淋巴细胞减少的模型）T1D的遗传因素。我们已经确定了五个基因座的位置

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.