CORM-2阻断核内HMGB1释放的机制及其在肾缺血再灌注损伤中的保护作用研究

肾缺血再灌注损伤（IRI）是急性肾衰最常见的原因。目前关于IRI的研究多在后期效应阶段，而对IRI早期如何启动的机制则研究尚少；对减轻IRI的保护方法和效果，也基本停留在可逆性IRI动物模型中的部分保护作用，仍不能应用在临床上。因此，迫切需要结合新的研究进展，重新探讨IRI的启动机制，寻找新的更有效的治疗靶点。近期发现，"危险相关分子模式"(DAMP)分子HMGB1从核内向核外释放后，可以级联激活炎症及免疫反应，在IRI的启动中发挥至关重要的作用。本课题组首次发现，外源性CO（CORM-2）可以阻断核内HMGB1向核外释放，逆转小鼠致死性IRI，肾功能损伤几乎得到完全保护。该发现在国内外尚未见类似报道。本项目拟在动物模型及原代细胞中，进一步研究CORM-2阻断核内HMGB1向核外释放的机制及其在肾缺血再灌注损伤中的保护作用，并探讨其潜在治疗靶点。

Kidney ischemia-reperfusion injury (IRI) is the most common cause of acute renal failure. The detail machanism and the trigger foctors of IRI are still not clear. The strategy reported to prevent IRI is still unsatisfactory. So we need to restudy the trigger machanism of IRI with new scientific progress. As a hotspot, HMGB1, one of DAMP molecules,has been proved an vital role in IRI by triggering inflammation and immunoreaction. Our research group firstly observed that CORMs,a carbon monoxide releasing molecules，could block the release of nuclear HMGB1 and reverse the severe lethal kidney ischemia-reperfusion injury. This is an important first discovery. This project will deeply study the machanism and signal pathway of this blocking appearance and its prevent effect in IRI by using siRNA, nucleoprotein extracting technique, immuno-precipitation, mensuration of enzyme and etc.