This Program Project application is based on our more than 6 years of ongoing collaborations to uncover the genes which control the development of spontaneous organ-specific autoimmune disease in the rat. Thin application constitutes three projects which are highly interactive to share resources including BB rats and proposed congenic lines, positional cloning reagents and expertise to provide cost saving research of genetic mechanisms of organ-specific autoimmunity. The Program Project investigators accomplishments include: 1) the establishment of the genetic map of the rat; 2) the mapping of the first diabetes gene (iddm1) to the lymphopenia (lyp) gene locus on chromosome 4 done in a cross between the inbred diabetes-prone (DP) and diabetes- resistant (DR) BB rats; 3) the development of a transspecies strategy to link the lymphopenia region to clone the lyp gene by position; 4) the linkage of the second diabetes gene (iddm2) to the major histocompatibility (MHC) gene locus (RT1BU) on chromosome 20 in a cross between DP BB rats and Lewis rats; 5) the preliminary and yet unpublished mapping in a cross with Fischer rats of a third diabetes gene (iddm3) to chromosome 2; 6) the evidence that the MHC (RT1.Bu/u) has a dominant susceptibility for thyroiditis and 6) the demonstration that the majority of the peripheral T cells pool in lyp/lyp rats consists of recent thymic emigrants with autoreactive properties. The projects are: Project 1: The P.I. will analyze the lymphopenia, insulitis and thyroiditis phenotypes using the above indicated strategy of BB rat breeding and cross-intercross analyses to produce congenic lyp/lyp, lyp/+ and +1+ BB DR and Fischer rats; Project 2: The P.I. will positionally clone lyp, characterize the expression of the lyp gene in the mouse and, in collaboration with Project 1, in the rat, and develop a mouse in which the lyp gene has been disrupted to replicate the lymphopenia phenotype: Project 3: The P.I. will analyze the third gene, iddm3, which confers susceptibility to diabetes and develop congenic animals for iddm3 as well as iddm1, clone and characterize iddm3 and identify other iddm genes with the use of the total genome scan strategy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI042380-02
Application #
2673162
Study Section
Allergy & Clinical Immunology-1 (AITC)
Project Start
1997-09-30
Project End
2000-08-31
Budget Start
1998-09-01
Budget End
1999-08-31
Support Year
2
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of Washington
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
135646524
City
Seattle
State
WA
Country
United States
Zip Code
98195
Jokinen, Riikka; Lahtinen, Taina; Marttinen, Paula et al. (2015) Quantitative changes in Gimap3 and Gimap5 expression modify mitochondrial DNA segregation in mice. Genetics 200:221-35
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
Moralejo, Daniel; Yanay, Ofer; Kernan, Kelly et al. (2011) Sustained glucagon-like peptide 1 expression from encapsulated transduced cells to treat obese diabetic rats. J Biosci Bioeng 111:383-7
Moralejo, Daniel H; Fuller, Jessica M; Rutledge, Elizabeth A et al. (2011) BB rat Gimap gene expression in sorted lymphoid T and B cells. Life Sci 89:748-54
Yanay, Ofer; Moralejo, Daniel; Kernan, Kelly et al. (2010) Prolonged survival and improved glycemia in BioBreeding diabetic rats after early sustained exposure to glucagon-like peptide 1. J Gene Med 12:538-44
Moralejo, Daniel H; Hansen, Carl T; Treuting, Piper et al. (2010) Differential effects of leptin receptor mutation on male and female BBDR Gimap5-/Gimap5- spontaneously diabetic rats. Physiol Genomics 41:9-20
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
Schulteis, Ryan D; Chu, Haiyan; Dai, Xuezhi et al. (2008) Impaired survival of peripheral T cells, disrupted NK/NKT cell development, and liver failure in mice lacking Gimap5. Blood 112:4905-14

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