Insulin dependent diabetes mellitus (IDDM) in the BB rat is a polygenic autoimmune disorder characterized by T cell-mediated destruction of pancreatic beta cells, insulinopenia, and hyperglycemia. Diabetic BB rats, like NOD mice, are used to model human IDDM. To date, the only known element common to the genetic control of IDDM in these species is the requirement for a permissive major histocompatibility complex (MHC) haplotype. Understanding the non-MHC genetic factors that influence the development of IDDM in BB rats is the goal of this proposal. To achieve this goal, we propose a combination of cell biological methods, traditional breeding strategies, and contemporary molecular mapping to identify loci responsible for susceptibility and resistance to IDDM. We take as a point of departure two recent discoveries that we have made. First, there are dominantly inherited thymic epithelial defects in the BB rat. These defects, absent in normal WF rats, are present in both lymphopenic and nonlymphopenic BB rats and in nonlymphopenic (DP x WF)F1 hybrids. We hypothesize that this form of thymic epithelial pathology allows the generation and release of autoreactive T cells. The second key discovery, directly supporting this hypothesis, is that transient in vivo depletion of the RT6+ T cell subset induces autoimmunity in nonlymphopenic (DP x WF)F1 and [(DP x WF)F1 x WF] rats that are otherwise disease free. A genetic association between thymic defects and IDDM will provide strong support for the prediction that thymic epithelial abnormalities are causally related to the development of autoreactive T cells that lead to autoimmunity. Using simple sequence length polymorphism (SSLP) methods and a technique for inducing selective lymphocyte depletion in the absence of type homozygosity, we will identify, localize, and characterize loci that govern diabetes resistance and susceptibility.
Specific Aim No. l is to create large segregating populations of (DP x WF)F1 x WF rats and the F2 intercross between (DP x WF)F1 rats.
Specific Aim No. 2 is to identify microsatellite marker alleles (SSLP) that are specific to DP-BB rats and histocompatible normal WF rats. These SSLPs will provide the genetic instrument needed to analyze the rats generated in Specific Aim #1.
Specific Aim No. 3 is to map the genetic loci that modify susceptibility to IDDM and that control specific traits we have shown to be etiologically related to the disease.
This Aim will be accomplished by linkage analysis of the data obtained in Specific Aims #1 and #2. Our belief and ultimate hope is that understanding the genetic basis for IDDM in BB rats will lead to the identification of analogous loci relevant to the pathogenesis and hence prevention of human IDDM.
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