This research will characterize and fine map the genes on rat chromosome 4 which control adjuvant-induced arthritis (AIA). QTL analysis of F2 hybrid offspring of (DA x F344)F2 hybrid rats has identified four QTLs associated with AIA severity - three of DA origin (Aia1, Aia2, and Aia3) and one of F344 origin (Aia4). Aia1 maps within the MHC on chromosome 20. Both Aia2 and Aia3 map to chromosome 4 and Aia4 maps to chromosome 15. Our laboratory is developing a consomic rat line by transferring the entire intact chromosome 4 from the Dark Agouti (DA) rat - which develops severe AIA - onto the background of the Fischer (F344) rat - which is relatively resistant to AIA. The F344.DA(Chr4) consomic rat line has sustained arthritis phenotype at the third backcross generation, indicating that the genes on chromosome 4 are highly prominent in AIA. This F344.DA(Chr4) consomic rat provides a unique model for investigating the genes on chromosome 4 which control arthritis severity in AIA.
Specific aim #1. Complete the development and phenotype testing of the chromosome 4 consomic line with DA chromosome 4 on F344 background - F344.DA(Chr4). Through directed breeding techniques that use genetic markers to include and exclude QTLs known to control arthritis severity, a chromosome 4 consomic rat line will be established in which chromosome 4 of DA origin is bred onto a F344 background - F344.DA(Chr4). The arthritis susceptibility, arthritis severity, and other phenotypic markers of arthritis related biologic pathways will be determined in this new rat line.
Specific aim #2. Construct consomic/congenic rat line with DA chromosome 4 and DA MHC. Through selective breeding with an MHC congenic rat - F344.DA(Aia1) which carries the DA MHC on a F344 background - a consomic/congenic rat line, F344.DA(Aia1,Chr4), will be created and phenotype profile associated determined.
Specific aim #3. Determine the phenotype profile associated with Aia2 and Aia3 in AIA. The F344.DA(Aia1,Chr4) rat carries Aia1, Aia2 and Aia3 of DA origin. Through selective breeding techniques, the combined and individual effects of Aia2 and Aia3 on AIA severity and sub- phenotype profiles will be determined.
Specific aim #4. Fine map the genes controlling AIA. Techniques as employed for the initial QTL analysis of the (DAxF344)F2 rats will be applied to F344.DA(Aia1) x F344.DA(Aia1,Chr4)F2 hybrids to produce high resolution maps (approximately 1 cM) for each major QTL. With the mapping of Aia2 and Afa3, potential candidate genes will be suggested.
| Meng, Hsiang-Chi; Griffiths, Marie M; Remmers, Elaine F et al. (2004) Identification of two novel female-specific non-major histocompatibility complex loci regulating collagen-induced arthritis severity and chronicity, and evidence of epistasis. Arthritis Rheum 50:2695-705 |
| Remmers, Elaine F; Joe, Bina; Griffiths, Marie M et al. (2002) Modulation of multiple experimental arthritis models by collagen-induced arthritis quantitative trait loci isolated in congenic rat lines: different effects of non-major histocompatibility complex quantitative trait loci in males and females. Arthritis Rheum 46:2225-34 |
| Joe, Bina; Cannon, Grant W; Griffiths, Marie M et al. (2002) Evaluation of quantitative trait loci regulating severity of mycobacterial adjuvant-induced arthritis in monocongenic and polycongenic rats: identification of a new regulatory locus on rat chromosome 10 and evidence of overlap with rheumatoid arthritis su Arthritis Rheum 46:1075-85 |
