WHY: The cause of juvenile (type 1) diabetes is still unknown. Its expression appears to require both genetic predisposition and an environmental, probably viral, trigger. Our goal is to identify the iddm17 gene, a critical non-MHC determinant of susceptibility to autoimmune diabetes following viral infection in the BBDR rat. In clean housing, BBDR rats never become diabetic, but infection with Kilham rat virus (KRV) induces the disease in 40%. Brief exposure to a non diabetogenic dose of poly I:C, a ligand of toll-like receptor 3, before infection increases the penetrance of autoimmune diabetes to 100%. Using this induction protocol, we have discovered a new BBDR locus (Iddm17) specifically required for virus-triggered diabetes. HOW: This is a revised application of reduced scope that is focused exclusively on identifying genes in the Iddm17 interval that govern the expression of autoimmune diabetes after viral infection. It will create the critical congenic rat resources needed to achieve that goal.
Specific Aim No. 1 is to create large segregating populations of (BBDR x WF)F2 rats. These will be used to complete a preliminary intercross study and genome-wide scan. Composite interval mapping will be performed and results will be used to define the Iddm17 interval for positional candidate identification in Aim 2.
Specific Aim No. 2 is to use marker-assisted procedures to generate congenic rats to fine map Iddm17. In these congenic animals, other dominant diabetes susceptibility genes will not be segregating. With these resources we will seek to identify the Iddm17 gene and test the hypothesis that the response of Iddm17 during viral infection is a critical determinant of autoimmune diabetes expression. WHO: To achieve our goals, we will continue a collaborative arrangement, between a cellular biologist at the University of Massachusetts Medical School and a molecular geneticist at the Drexel University College of Medicine. Their complementary activities have generated the preliminary data that form the basis of this application. WHEN: We believe we will be able to identify the Iddm17 gene within 3 years. BOTTOM LINE: While centered on studies of diabetic rats, the importance of this proposal is its relevance to human juvenile diabetes. NIH and JDRF have established both a human type 1 diabetes genetics consortium to identify susceptibility genes and the """"""""Triggers and Environmental Determinants in Diabetes of the Young"""""""" project. The work we propose, identifying the Iddm17 gene, has the potential to contribute importantly to the goals of both of those endeavors.
| Fuller, J M; Bogdani, M; Tupling, T D et al. (2009) Genetic dissection reveals diabetes loci proximal to the gimap5 lymphopenia gene. Physiol Genomics 38:89-97 |
| Pino, Steven C; O'Sullivan-Murphy, Bryan; Lidstone, Erich A et al. (2009) CHOP mediates endoplasmic reticulum stress-induced apoptosis in Gimap5-deficient T cells. PLoS One 4:e5468 |
