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Comprehensive regulatory system of PAMPs/DAMPs by TM-PC/EPCR system

TM-PC/EPCR 系统对 PAMPs/DAMPs 的综合调控体系

基本信息

批准号：
24659798
负责人：
MARUYAMA Ikuro
金额：
$ 2.41万
依托单位：
Kagoshima University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Challenging Exploratory Research
财政年份：
2012
资助国家：
日本
起止时间：
2012 至无数据
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-24659798/
关键词：
PAMPs DAMPs トロンボモジュリンプロテインC HMGB1 PAMPｓ

项目摘要

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.

内皮血栓调节蛋白（TM）结合DAMP（损伤相关分子模式）; HMGB 1，代表DAMP，组蛋白。此外，TM还将PAMPs（病原体相关分子模式）;脂多糖（LPS），一种代表性的PAMPs，结合到分子的凝集素样结构域上，并中和它们的细胞病变活性，包括促炎和促凝血活性。HMGB 1与TM结合后被凝血酶/TM复合物降解，产生N端缺失的HMGB 1，命名为des-HMGB 1。Des-HMGB 1与受体TLR 2 -2、TLR 4结合。然而，与完整的HMGB 1相比，其结合亲和力较弱，这表明该分子的脱型可能在HMGB 1及其受体之间形成负反馈环，调节HMGB 1的多种活性。因此，检测des-HMGB 1的表达水平，可为DIC、脓毒症、全身炎症反应综合征（SIRS）等疾病的诊断提供重要信息，因此，我们尝试建立des-HMGB 1的特异性检测方法。我们制备了特异性单克隆抗体与des-HMGB 1反应。利用该单克隆抗体建立了特异性的酶联免疫吸附试验（ELISA）。ELISA成功地检测了10%污染的完整形式的des-HMGB 1。DIC患者血清中Des-HMGB 1水平升高，以TM组升高更为明显。然而，增加的des-HMGB 1迅速下降，表明des-form的快速转换。此外，一些患者甚至用重组TM治疗也没有显示des-HMGB 1增加，这表明存在无应答病例。因此，des-HMGB 1的检测有望为DIC、SIRS、脓毒症等疾病的治疗提供新的信息。