Pathogenomics of collagen disease using synthetic polymorphic proteins and BAG transgenic mice

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Collagen disease involving SLE and RA shows a complex pathological manifestation such as glomerulonephritis, vasculitis, arthritis and/or sialoadenitis, which seems to result from the cumulative effect of multiple gene loci with an allelic combination. In this research, we focused on to identify these genes in MRL model mice.MRL/MpJ-lpr/lpr mice bearing a Fas deletion mutant gene lprr (MRL/lpr), spontaneously develop various forms of collagen disease in the same individuals, including glomerulonephritis, polyarteritis, arthritis and sialoadenitis, associated with an MRL background. Previously, we mapped susceptibility loci to each lesion with polymorphic microsatellite markers using N2 backcross and F2 intercross mice with C3H/lpr mice, and clarified that gene loci responsible for each lesion exist at different chromosomal positions and they have additive and hierarchical properties in a polygenic manner. To identify the candidate genes for each locus, we performed novel strategies. 1) functional analyses of synthetic polymorphic proteins corresponding to the candidate genes in vitro, 2) development of recombinant inbred strains of mice between MRL/lpr and C3H/lpr mice and the strain distribution pattern table, followed by the pathogenimics studies, 3) development of transgenic mice with BAG (bacterial artificial chromosomes) corresponding to the positional candidate loci, followed by the pathological analyses.We conclude that these studies were efficient to clarify the susceptibility genes to polygenic diseases involving collagen disease based on functional genomics.