Rats are an important experimental model for many human diseases, many of which have a genetic component. We are mapping the genomic locations of genes that regulate the development of experimental autoimmune arthritis and related diseases in rats because it is highly likely that this information will facilitate the identification of similar genes or related biochemical pathways in humans and may lead to novel therapies for various autoimmune diseases. OBJECTIVES: This project has several components: 1) development of dense genetic linkage, radiation hybrid, physical and transcription maps of the rat applicable to autoimmune disease-prone and -resistant inbred rat strains; 2) development of comparative genomic maps among rats, mice and humans; 3) generation and phenotypic characterization of experimental crosses of autoimmune disease-prone and -resistant inbred strains; 4) linkage analysis to identify genomic regions containing disease regulatory genes; 5) development and analysis of congenic inbred rat strains carrying disease resistance genes on a susceptible background or vice versa to facilitate fine mapping and analysis of functional effects. RESULTS: We have continued to work on the development of a dense genetic linkage map applicable to the rat strains in which we are interested (DA, LEW, BB (DR), F344, BN, ACI). We have further increased the density of markers on our integrated rat genetic linkage map. Over 1100 markers, including 196 new markers developed by our group plus 240 genes, have been mapped in various crosses. These crosses include: DA x F344 (531 markers), LEW x F344 (673 markers), LEW x BN (714 markers), DA x BN (194 markers), and DA x ACI (246 markers). We are working actively to integrate our maps with those of other groups. Additional work is in progress for several chromosomes in the development of a radiation hybrid map that incorporates many of our markers, as well as many markers that could not be mapped by linkage methods. Some of this information has been published or made available through a website (www.nih.gov/niams/scientific/ratgbase/). We previously reported the localization, by linkage techniques, of the rat osteopetrosis (op) mutation to the distal end of rat Chr10. We have continued our efforts to positionally clone the mutant disease gene. Additional markers in the vicinity of the op gene have been identified and the development of a radiation hybrid map in this region is in progress. The location of op gene has now been mapped to a 0.7 cM interval. A candidate gene has been identified and is currently being evaluated. Identification of the op gene is important because it appears to represent a defect in an osteoclast differentiation pathway that has not been previously characterized. The majority of our efforts have been focused on identifying and refining the locations of Quantitative Trait Loci (QTL) regulating phenotypes related to collagen-induced arthritis (CIA) and adjuvant arthritis. For CIA, we have identified 14+ QTL (Cia1-14) that regulate disease severity. We have also identified 3 loci that regulate antibody titer (Ciaa1-3). For adjuvant arthritis, we have identified 5 QTL (Aia1-5). Interestingly, QTL on Chr4, Chr7, Chr10, Chr12 and Chr20 appear to be involved in the regulation of multiple experimental forms of autoimmune disease in rats, in addition to arthritis. The homologous locations in mice humans also appear to contain regulatory genes for various forms of autoimmune diseases. Several papers describing some of this work were published this past year. In collaboration with Rachel Caspi (NEI), we have also identified regulatory loci on Chr4 and Chr12 that regulate experimental autoimmune uveitis and published a paper describing these results. Further analysis of this work is in progress through the development of congenic lines. CONCLUSIONS: The genetic mapping data support our view that several QTL harbor genes common to multiple autoimmune diseases. Analysis of QTL-congenic rat strains, which is now in progress, should allow us to address in much greater depth the hypothesis that variant forms of several immunoregulatory genes play a role in multiple forms of autoimmune disease and may provide an explanation for clustering of distinct autoimmune diseases in families.

Project Start
Project End
Budget Start
Budget End
Support Year
9
Fiscal Year
2000
Total Cost
Indirect Cost
Name
Arthritis, Musculoskeletal, Skin Dis
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Dracheva, S V; Remmers, E F; Chen, S et al. (2000) An integrated genetic linkage map with 1,137 markers constructed from five F2 crosses of autoimmune disease-prone and -resistant inbred rat strains. Genomics 63:202-26
Brodkin, E S; Kosten, T A; Haile, C N et al. (1999) Dark Agouti and Fischer 344 rats: differential behavioral responses to morphine and biochemical differences in the ventral tegmental area. Neuroscience 88:1307-15
Joe, B; Griffiths, M M; Remmers, E F et al. (1999) Animal models of rheumatoid arthritis and related inflammation. Curr Rheumatol Rep 1:139-48
Shepard, J S; Remmers, E F; Chen, S et al. (1999) A genetic linkage map of rat Chromosome 15 derived from five F2 crosses. Mamm Genome 10:186-8
Dracheva, S V; Remmers, E F; Gulko, P S et al. (1999) Identification of a new quantitative trait locus on chromosome 7 controlling disease severity of collagen-induced arthritis in rats. Immunogenetics 49:787-91
Wilder, R L; Griffiths, M M; Remmers, E F et al. (1999) Localization in rats of genetic loci regulating susceptibility to experimental erosive arthritis and related autoimmune diseases. Transplant Proc 31:1585-8
Griffiths, M M; Remmers, E F; Cannon, G W et al. (1999) MHC and non-MHC genes in the regulation of susceptibility to collagen-induced arthritis among DA, BB, and BN rats. Transplant Proc 31:1589
Remmers, E F; Griffiths, M M; Longman, R E et al. (1999) An integrated rat genetic map: analysis of linkage conservation with the mouse and human maps. Transplant Proc 31:1549-54
Sun, S H; Silver, P B; Caspi, R R et al. (1999) Identification of genomic regions controlling experimental autoimmune uveoretinitis in rats. Int Immunol 11:529-34
Griffiths, M M; Encinas, J A; Remmers, E F et al. (1999) Mapping autoimmunity genes. Curr Opin Immunol 11:689-700