| Co-Investigator(Kenkyū-buntansha) |
NATATSURU Shuichi KAN Research Institute, Genome Research, Head, ゲノム研究室, 室長
LU Ling-Min Ehime University, Faculty of Medicine, Instructor, 医学部, 助手 (80304616)
MIYAZAKI Tatsuhiko Ehime University, Faculty of Medicine, Instructor, 医学部, 助手 (80239384)
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| Budget Amount *help |
¥5,400,000 (Direct Cost: ¥5,400,000)
Fiscal Year 2000: ¥5,400,000 (Direct Cost: ¥5,400,000)
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| Research Abstract |
The pathological findings in collagen disease involving SLE and RA show complex lesions such as glomerulonephritis, vasculitis, arthritis and/or sialoadenitis, which have resulted in confusion in distinctly categorizing collagen diseases. It is still controversial whether such diversity and similarity of pathological manifestations among the collagen disease depends on ambiguity in diagnosis or is an intrinsic quality of the collagen diseases themselves. In this research, we focused on this subject based on a genetic aspect and studied genomics of a murine model, an MRL strain.
MRL/MpJ-lpr/lpr mice bearing a Fas deletion mutant gene lpr(MRL/lpr), spontaneously develop various forms of collagen disease in the same individuals, including glomerulonephritis, polyarteritis, arthritis and sialoadenitis. These diseases are not a single gene disease involving the complex pathological manifestations as pleiotropy, and particular gene(s)of MRL background are required for affecting the developmen
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t of each lesion. Association studies of each lesion with polymorphic microsatellite markers using N2 backcross and F2 intercross mice with C3H/lpr mice revealed that gene loci responsible for each lesion exists at different chromosomal positions and they have additive and hierarchical properties on polygenic inheritance for some of the lesions. Moreover, some of susceptibility loci to systemic vasculitis showed the specificity for the caliber of arteries. Candidate gegnes in each locus involved CD72 for vasculitis and glomerulonephritis, and osteopontin(OPN)for glomerulonephritis. Synthetic polymorphic proteins of OPN were different in the ability to induce B cells activation between both strains^1. Some mice in the backcross progeny with a wild inbred strain of mice MSM/Msf, which is genetically one million year distant from an MRL strain, developed a novel arthropathy in foot joints, characteristic of chondrohyperplasia, which was under the control of a susceptible locus on Chr.18 in a heterozygous inheritance.
We conclude that the complex pathological manifestations of collagen disease are under the control of different combinations of polygenes involving allelic polymorphism. Less
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