Collagen-induced arthritis is a well-established experimental animal model of arthritis that has been used to gain insight into the pathogenesis of rheumatoid arthritis. The overall objective of this proposal is to identify the non-MHC genes that regulate development of this form of experimental arthritis. In experiments that led up to present proposal, advantage was taken of the fact that two inbred rat strains sharing the same MHC haplotype, RT1av1, differed strikingly in their susceptibility to arthritis induced with homologous rat type II collagen, although both strains exhibited the production of collagen autoantibodies. A genome-wide scan in a F2 cross between arthritis-susceptible DA and arthritis-resistant ACI rats identified one non-MHC DA- originated quantitative trait locus (QTL), Cia7, on rat chromosome 2, and two other suggestive loci on chromosome 2 and 10. A significant sex effect was also identified. These three loci map to genomic intervals syntenic to regions previously identified in the mouse and human genomes containing genes involved in the susceptibility to different forms of autoimmune diseases, further emphasizing the relevance of this study. This proposal hypothesizes that the three QTL described above contain genes that act to convert the state of asymptomatic autoimmunity induced by the collagen immunization into a frank autoimmune disease.
The first aim i s construction of genotype-guided speed congenic rats, introducing DA segments into ACI background, and vice-versa. Sex interaction with the three QTL will be studied in the congenic animals. At later stages, polycongenic rats will be generated to determine the interaction of the three loci.
The second aim i s identification of the genes. In order to accomplish this goal, two basic approaches will be used. First, a candidate gene strategy will be employed, taking advantage of mouse and human genome homology mapping data, and screening candidate gene exons for mutations, followed by sequencing, when applicable. Differential expression of certain candidate genes will be analyzed in cDNA libraries generated from synovial tissue and T cells. The second strategy will follow a more standard approach, first narrowing the congenic interval to 1 cM through generation of recombinants, followed by isolation of transcripts in the regions, cloning and sequencing. Both of these strategies will be supplemented by identification of candidate surrogate immunologic sub-phenotypes involved in the response that should provide both insight into the mechanism of gene action and alternative markers for immunologic phenotypes thus facilitating the gene discovery process.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
7R01AR046213-04
Application #
6557988
Study Section
General Medicine A Subcommittee 2 (GMA)
Program Officer
Gretz, Elizabeth
Project Start
1999-09-15
Project End
2004-06-30
Budget Start
2001-10-01
Budget End
2002-06-30
Support Year
4
Fiscal Year
2001
Total Cost
$211,341
Indirect Cost
Name
North Shore University Hospital
Department
Type
DUNS #
City
Manhasset
State
NY
Country
United States
Zip Code
11030
Laragione, Teresina; Cheng, Kai F; Tanner, Mark R et al. (2015) The cation channel Trpv2 is a new suppressor of arthritis severity, joint damage, and synovial fibroblast invasion. Clin Immunol 158:183-92
Guo, Xiaosen; Brenner, Max; Zhang, Xuemei et al. (2013) Whole-genome sequences of DA and F344 rats with different susceptibilities to arthritis, autoimmunity, inflammation and cancer. Genetics 194:1017-28
Brenner, Max; Laragione, Teresina; Gulko, Pércio S (2013) Arthritis severity locus Cia4 is an early regulator of IL-6, IL-1?, and NF-?B activators' expression in pristane-induced arthritis. Physiol Genomics 45:552-64
Brenner, Max; Laragione, Teresina; Gulko, Pércio S (2013) Analyses of synovial tissues from arthritic and protected congenic rat strains reveal a new core set of genes associated with disease severity. Physiol Genomics 45:1109-22
Jenkins, E; Brenner, M; Laragione, T et al. (2012) Synovial expression of Th17-related and cancer-associated genes is regulated by the arthritis severity locus Cia10. Genes Immun 13:221-31
Brenner, Max; Laragione, Teresina; Shah, Anish et al. (2012) Identification of two new arthritis severity loci that regulate levels of autoantibodies, interleukin-1?, and joint damage in pristane- and collagen-induced arthritis. Arthritis Rheum 64:1369-78
Brenner, Max; Linge, Carl P; Li, Wentian et al. (2011) Increased synovial expression of nuclear receptors correlates with protection in pristane-induced arthritis: a possible novel genetically regulated homeostatic mechanism. Arthritis Rheum 63:2918-29
Laragione, Teresina; Brenner, Max; Sherry, Barbara et al. (2011) CXCL10 and its receptor CXCR3 regulate synovial fibroblast invasion in rheumatoid arthritis. Arthritis Rheum 63:3274-83
Laragione, Teresina; Gulko, Percio S (2010) mTOR regulates the invasive properties of synovial fibroblasts in rheumatoid arthritis. Mol Med 16:352-8
Johannesson, Martina; Lopez-Aumatell, Regina; Stridh, Pernilla et al. (2009) A resource for the simultaneous high-resolution mapping of multiple quantitative trait loci in rats: the NIH heterogeneous stock. Genome Res 19:150-8

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