Rats are an important experimental model for many human diseases, many of which have a genetic component. We are interested in mapping the genomic locations of genes that regulate the development of experimental autoimmune arthritis and related diseases in rats because we suspect that this information will facilitate the identification of similar genes or related biochemical pathways in humans. OBJECTIVES: This project has several components: 1) development of dense genetic, 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 map applicable to the rat strains in which we are interested (DA, LEW, BB (DR), F344, BN, ACI). We have developed integrated maps involving 5 crosses. Some of this information has been published or made available through a website (www.nih.gov/niams/scientific/ratgbase/). Over 1100 markers have been mapped in various crosses. We are working actively to integrate our maps with those of other groups. We previously reported the mapping of the rat osteopetrosis (op) mutation to the distal end of rat Chr10. We have continued our efforts to positionally clone the disease gene. The location of op gene has been mapped to a 0.7 cM interval on Chr10. 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 are focused on identifying and refining the locations of Quantitative Trait Loci (QTLs) regulating phenotypes related to collagen-induced arthritis (CIA) and adjuvant arthritis (in collaboration with M. Griffiths and G. Cannon). For CIA, we have identified 10 QTLs (Cia1-10), which meet stringent criteria, that regulate disease. For adjuvant arthritis, we have identified 3 QTLs (Aia1-3). Interestingly, QTLs on Chr4 and Chr20 appear to be involved in the regulation of both experimental forms of autoimmune disease. Several manuscripts describing this work are now in press. In collaboration with Rachel Caspi (NEI), we have also identified regulatory loci on Chr4 and Chr12 that regulate experimental autoimmune uveitis. The mapping data support our view that some QTLs harbor genes common to multiple autoimmune diseases. Analysis of QTL-congenic rat strains, which we are developing, should allow us to address 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.
