2012 Fiscal Year Final Research Report
Comprehensive regulatory system of PAMPs/DAMPs by TM-PC/EPCR system
| Project/Area Number |
24659798
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| Research Category |
Grant-in-Aid for Challenging Exploratory Research
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| Allocation Type | Multi-year Fund |
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| Research Field |
Emergency medicine
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| Research Institution | Kagoshima University |
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Principal Investigator |
MARUYAMA Ikuro 鹿児島大学, 大学院・医歯学総合研究科, 特任教授 (20082282)
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| Co-Investigator(Kenkyū-buntansha) |
ITO Takashi 鹿児島大学, 大学院・医歯学総合研究科, 特任講師 (20381171)
TERUTO Hashiguchi 鹿児島大学, 大学院・医歯学総合研究科, 教授 (70250917)
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| Co-Investigator(Renkei-kenkyūsha) |
KAWAHARA Ko-ichi 大阪工業大学, 工学部生命工学科, 特任教授 (10381170)
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| Research Collaborator |
YAMADA Shingo 株式会社シノテスト
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| Project Period (FY) |
2012
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| Keywords | PAMPs / DAMPs / トロンボモジュリン / プロテインC / HMGB1 |
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| Research Abstract |
Endothelial thrombomodulin(TM) bounds DAMPs(Damage Associated Molecular Patterns);HMGB1,a representative DAMPs, histones. Moreover TM also bounds PAMPs(Pathogen Associated Molecular Patterns) ;lipopolysaccaride(LPS), a representative PAMPs, onto the lectin-like domain of the molecule and neutralizes their cytopathic activities, including proinflammatory and procoagulant activities. HMGB1 bound to TM, degraded by thrombin/TM complex and generated the N-terminus deleted HMGB1, named as des-HMGB1. Des-HMGB1 bound onto the receptors RAGE and TLR2-2, -4. However the binding affinity was weak compared to intact HMGB1, suggesting des-form of the molecule may configure a negative feedback loop among HMGB1 and its receptors regulating the diverse activities of HMGB1. Based on the findings, assay of des-HMGB1.may provide significant information in such morbid states including Disseminated Intravascular Coagulation(DIC), sepsis, systemic inflammatory response sybdrome(SIRS) and so on. Therefore we tried to establish specific assay method of des-HMGB1. We got specific monoclonal antibodies to react with the des-HMGB1. Using the monoclonal antibody, we established specific enzyme linked immune sorbent assay(ELISA). The ELISA successfully detected des-HMGB1 with 10% contamination of intact form. Des-HMGB1 was increased the serum from DIC, especially treated with recombinant TM. However the increased des-HMGB1 was decreased rapidly suggesting the rapid turn-over of the des-form. Moreover some patients showed no increased in des-HMGB1 even with recombinant TM treatment, suggesting of the presence or non-responder cases. Thus assessment of des-HMGB1 may be expected to provide a novel information in the DIC, SIRS, sepsis and so on with or without treatment.
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