| Project/Area Number |
17590348
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Experimental pathology
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| Research Institution | Ehime University |
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Principal Investigator |
MIYAZAKI Tatsuhiko Ehime University, Graduate School of Medicine, Professor, 大学院・医学系研究科, 助教授 (80239384)
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| Co-Investigator(Kenkyū-buntansha) |
NOSE Masato Ehime University, Graduate School of Medicine, Professor, 大学院・医学系研究科, 教授 (70030913)
KAMEDA Kenji Ehime University, Integrated Center for Sciences, Lecturer, 総合科学研究支援センター, 講師 (60363264)
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| Project Period (FY) |
2005 – 2006
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| Project Status |
Completed (Fiscal Year 2006)
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| Budget Amount *help |
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2006: ¥1,000,000 (Direct Cost: ¥1,000,000)
Fiscal Year 2005: ¥2,600,000 (Direct Cost: ¥2,600,000)
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| Keywords | Osteopontin / Structural polymorphism / Promoter polymorphism / Congenic mice / Cell free protein synthesis |
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| Research Abstract |
We previously identified Opn as a candidate gene susceptible to glomerulonephritis in MRL/lpr mice by genome wide screening using (MRL/lpr x C3H/lpr)F_2 mice, followed by a functional assay of synthetic polymorphic OPN peptides of MRL and C3H type. Also we clearly indicated that the MRL-OPN induced higher expression and production of immunoglobulins as well as cytokines including TNF-alpha, IL-lbeta and IFN-gamma in splenocytes and/or macrophages than that of the C3H allele. These findings suggest that allelic polymorphism of OPN causes the functional differences in antibody production and macrophage activation between MRL and C3H strains, possibly involved in the development of lupus nephritis. On the other hand, Opn expression level in autoimmune prone mice were reported higher than that in disease resistant mice, in vitro. To determine whether qualitative (functional) difference or quantitative difference of Opn implicated in the development of autoimmune disease, we carried out the analyses as follows: 1) we generated mutant Opn peptides which were modified in substituted amino acid between two alleles followed by functional analyses of cell binding affinity 2) To determine the allelic difference of Opn expression in vivo, we made selective recombinant congenic mice of Opn gene locus which have C3H allele Opn in MRL background, 3) and then, carried out precise analyses of recombinant congenic mice.
1) Amino acid substitution by allelic polymorphism modified cell binding affinity of Opn.
2) The expression level of Opn was manifested to be controlled by Opn allele.
3) Incidence and severity of glomerulonephritis as well as livability of individuals probably via modification of cytokine properties which includes Th1/Th2 balance.
These results suggest that an amino acid substitution in allelic polymorphism of murine Opn as well as that in promoter polymorphism may play a critical role for the development of glomerulonephritis in MRL/lpr mice.
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