GENETIC ANALYSIS AND CHARACTERIZATION OF IDDM GENES

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Insulin-dependent (type I) diabetes mellitus (IDDM) is a significant public health problem with incidence ranging from 0.3 to 1 % in different populations. Despite intensive investigation, the etiology of IDDM remains unclear. IDDM clearly involves an autoimmune response against the pancreatic beta-cells. Studies in the human, mouse and rat indicate that a gene or genes in the major histocompatibility complex (MHC) account for some of the inherited predisposition to the disease, and that other genes besides MHC are involved in the pathogenesis of IDDM. The BioBreeding (BB) rat is known to be among the best animal models of IDDM with onset and pathogenesis closely resembling the human IDDM except for lymphopenia, and we have been characterizing the BB rat physiologically and genetically as a model for IDDM. Previously we have demonstrated that at least three genes are responsible for development of IDDM in the BB rat based on genetic analysis of several crosses (between the BB and the non-IDDM rat): Iddm1 (Lyp), which is tightly linked to the neuropeptide Y (Npy) gene on chromosome 4, Iddm2 linked to MHC on chromosome 20, and Iddm3 for which the Fischer (F344) rat strain carries an allele conferring resistance. After this study, we set out new crosses between the BB rat and the F344 rat. Then, we have recently mapped Iddm3 on chromosome 2. Therefore, next phase of this study is to clone Iddm3 by position, and to characterize their functions and physiological roles. Accordingly, we propose three specific aims for Project 3 in this PPG application: 1. Develop Congenic Animals for Iddm3. Once the genetic predisposition in the BB rat is identified, continued physiological characterization is essential to get better understanding of these genes. One way to accomplish this goal is to develop congenic animals. In this grant proposal, we will develop one Iddm3 congenic line. We will also develop two Iddml congenic lines with Project 1. 2. Clone and Characterize Iddm3. Since the Rat Genome Project is providing tools for the positional cloning, such as dense genetic map and large insert library, positional cloning strategy in the rat is now tractable. We will carry out homology mapping to identify human homologue for Iddm3. 3. Identify other Iddm genes with the Use of the Total Genome Scan Strategy. We have identified Iddm3 on chromosome 2. Our data has also suggested that Iddm3 could be a modifier and other Iddm genes could be involved in. In addition, there was gender difference with skipping-generation effect, suggesting potential involvement of epigenetic factors. We will continue to study these cross as well as more animals that are now being generated to provide more statistical power to identify other Iddm genes as well as to investigate the involvement of epigenetic factors.