Understanding of the mechanisms by which T1D develops is critical to prediction, prevention and cure. The spontaneously diabetic BB rat is particularly well suited for this task. In contrast to the complexity of human and NOD mouse T1D, onset in the BB rat is limited to five genes; the MHC on chromosome 20 (Iddm1), lyp (Ian5) (Iddm2) on chromosome 4 and three susceptibility factors on chromosomes 2 (IddmS), 4 (Iddm4) and 15 (Iddm19). Our discovery in 2002 of the frameshift mutation in Ian5 (IAN4L1) that results in lymphopenia uncovered a previously unknown family of Ian genes that appear to regulate apoptosis. This program project represents three highly interactive laboratories (Seattle and Milwaukee) and one administrative core (Seattle); Project 1: Ake Lernmark will collaborate with Projects 2 and 3 to test the hypotheses that a) coordinate expression of the Ian family controls lymphocyte differentiation and maturation to generate autoreactive T cells and b) identify and characterize the three genetic factors IddmS, Iddm4 and iddm19 that confer diabetes risk. Project 2: Hartmut Weiler and Michael Michalkiewicz will collaborate with Projects 1 and 3 by (a) completing the mouse knockout (KO) of Ian5, Ian4 alone and in combination to recapitulate the diabetogenic phenotype in the mouse; (b) rescuing the expression of Ian genes in transgenic rats and (c) establish Ian anti-apoptopic activity in rat and mouse transgenic animals. Project 3: Anne Kwitek and Marty Hessner will use genomic and microarray technologies to facilitate identification of chromosome 2,15 and 4 T1D susceptibility factors in collaboration with Project 1 and 2. Our research interactions are well established and shared resources will include BB, F344 and congenic rats (Project 1), congenic lines of mice with homologous recombination of Ian genes and rat transgenic rescue of lymphopenia (Project 2), high throughput genotyping for speed congenic lines (Projects 1 and 3), microarray analysis (Project 3), quantitative RT-PCR (Project 1) and virtual mapping between human, mouse, and rat (Project 3).

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI042380-11
Application #
7193487
Study Section
Special Emphasis Panel (ZAI1-SV-I (M1))
Program Officer
Johnson, David R
Project Start
1997-09-30
Project End
2010-01-31
Budget Start
2007-02-01
Budget End
2008-01-31
Support Year
11
Fiscal Year
2007
Total Cost
$946,153
Indirect Cost
Name
University of Washington
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
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Bogdani, Marika; Henschel, Angela M; Kansra, Sanjay et al. (2013) Biobreeding rat islets exhibit reduced antioxidative defense and N-acetyl cysteine treatment delays type 1 diabetes. J Endocrinol 216:111-23
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Kaldunski, Mary; Jia, Shuang; Geoffrey, Rhonda et al. (2010) Identification of a serum-induced transcriptional signature associated with type 1 diabetes in the BioBreeding rat. Diabetes 59:2375-85
Rutledge, Elizabeth A; Fuller, Jessica M; Van Yserloo, Brian et al. (2009) Sequence variation and expression of the Gimap gene family in the BB rat. Exp Diabetes Res 2009:835650
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
Sweet, Ian R; Yanay, Ofer; Waldron, Lanaya et al. (2008) Treatment of diabetic rats with encapsulated islets. J Cell Mol Med 12:2644-50

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