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 as new biomarkers for diagnosis and prognosis. In experiments leading up to the present proposal, a genome-wide screen done in an F2 intercross between the MHC identical arthritis- susceptible DA and the arthritis-resistant ACI inbred rat strains studied for CIA identified three non-MHC quantitative trait loci (QTL) Cia7, C/a70and C/a27on chromosomes 2, 2, and 10, respectively. Genotype- guided QTL-congenic strains were generated. DA.ACI(CialO) rats developed a significantly milder form of arthritis, typically with no synovial hyperplasia or pannus formation, and preservation of the joint architecture, compared with DA. The transfer of the Cia27 interval from DA into ACI.DA(Cia27) congenics, was enough to render these rats susceptible to CIA. Thus, it is hypothesized that the robust and highly penetrant phenotype of CIA and PIA depends on the presence of susceptibility alleles at Cia7, C/a70and Cia27. Additionally, Cia7, C/a70and C/a27are located in regions syntenic to those containing loci regulating different forms of autoimmune diseases, including RA, suggesting that these rat genes will be relevant to human disease. This proposal aims at identifying and characterizing those genes.
In Aim 1 the critical regions containing the arthritis genes will be progressively reduced to <1 Mb in recombinant subcongenics. Sub-phenotypes relevant to arthritis will continue to be identified and will be studied in congenics to obtain early clues to gene function and identity.
In Aim 2 candidate genes within the critical regions of C/a70and C/a27will be sequenced and analyzed for disease-causing polymorphisms/mutations that differentiate DA from ACI. The identified genes and alleles will be functionally characterized in in vitro and in vivo studies.
|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|
Showing the most recent 10 out of 22 publications