Collagen-induced arthritis (CIA) and pristane-induced arthritis (PIA) in rats are well-established experimental animal models that have been used to gain insight into the pathogenesis of rheumatoid arthritis (RA), a chronic and commonly disabling disease with a prevalence of 1% in most populations. CIA, PIA and RA are complex trait diseases regulated by MHC and non-MHC genes. Non-MHC genes account for 50-75% of the genetic contribution to RA, yet, little is known about those genes. The underlying hypotheses of this proposal are that the non-MHC loci governing susceptibility to and severity of CIA and PIA in rats will be highly relevant to understanding the pathogenesis of RA and could generate new targets for the development of more specific therapies, as well new tools for diagnosis and prognosis. In experiments leading up to the present proposal, a genome-wide screen done in a F2 intercross between the MHC discordant inbred arthritis-susceptible DA and the arthritis-resistant F344 rat strains identified three non-MHC quantitative trait loci (QTL) Cia3, Cia5 and Cia6 on chromosomes 4, 10 and 8, respectively. The arthritis-regulatory effect of these QTLs was confirmed in genotype-guided congenic strains where the F344-derived interval was introgressed into the DA background. These QTL-congenic strains were protected and developed a significantly milder form of arthritis. Based on these prior studies, it is hypothesized that the robust and highly penetrant phenotype of CIA and PIA depends on the presence of susceptibility alleles at Cia3, Cia5 and Cia6. Additionally, Cia3 and Cia5 are located in regions homologous to those containing RA susceptibility genes, suggesting that the same genes might regulate arthritis on both species. This proposal aims at identifying and characterizing those genes.
On aim 1 the construction of subcongenic strains will be completed in order to reduce the critical regions containing the arthritis genes to <1Mb. Subphenotypes relevant to arthritis will be identified and studied in congenics to obtain early clues to gene function and identity.
On aim 2 candidate genes within the critical regions will be sequenced and analyzed for disease-causing polymorphisms/mutations that differentiate DA from F344. The identified genes and disease variants will be functionally characterized in in vitro and in vivo studies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR052439-05
Application #
7664476
Study Section
Arthritis, Connective Tissue and Skin Study Section (ACTS)
Program Officer
Mao, Su-Yau
Project Start
2005-09-22
Project End
2010-08-31
Budget Start
2009-09-01
Budget End
2010-08-31
Support Year
5
Fiscal Year
2009
Total Cost
$337,306
Indirect Cost
Name
Feinstein Institute for Medical Research
Department
Type
DUNS #
110565913
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
Brenner, Max; Gulko, Pércio S (2012) The arthritis severity locus Cia5a regulates the expression of inflammatory mediators including Syk pathway genes and proteases in pristane-induced arthritis. BMC Genomics 13:710
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

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