急性肺损伤时HMGB1调控iPS和中性粒细胞竞争性组织归巢的作用及机制研究

项目名称： 急性肺损伤时HMGB1调控iPS和中性粒细胞竞争性组织归巢的作用及机制研究

项目编号： No.81470260

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 向萌

作者单位： 复旦大学

项目金额： 70万元

中文摘要： 中性粒细胞（PMN）的浸润是急性肺损伤的关键事件之一。我们证实高迁移率族蛋白（HMGB1）在调控PMN的组织浸润中起到重要作用；诱导性多能干细胞（iPS）治疗可缓解PMN浸润，减轻急性肺损伤。研究表明整合素α4β1是介导PMN与内皮细胞粘附的重要分子之一。我们最新发现抑制iPS整合素α4β1的表达，显著降低了iPS在多种损伤组织中的归巢。据此假设HMGB1可调控PMN与iPS的竞争性组织浸润和归巢。本项目拟通过左侧肺缺血再灌注损伤，结合外周血PMN去除和回输，利用微流控芯片、转基因及RNA干扰等技术，明确HMGB1对iPS和PMN在肺组织竞争性浸润和归巢的调控；进而检测HMGB1中和抗体存在的条件下，PMN和过表达整合素α4β1的iPS，以及在HMGB1刺激时，PMN和抑制整合素α4β1的iPS在细胞水平和肺损伤模型中的竞争性归巢作用，为提高iPS治疗效果提供潜在的新手段。

中文关键词： 诱导性多能干细胞；中性粒细胞；急性肺损伤；竞争性归巢；HMGB1

英文摘要： Neutrophil infiltration is one of the key events of acute lung injury. Our previous research confirmed that the high mobility group protein (HMGB1) in the regulation of neutrophils (PMN) play an important role in tissue infiltration; induced pluripotent stem (iPS) cells transplantion ameliorate ischemia-reperfusion injury of lung by inhibiting PMN infiltration. Furthermore, studies have shown that integrin α4β1 is the important molecular for PMN ahesion with endothelial cell.Interesting, our newly researches revealed that the protection has been inhibited in the injuried tissue by downregulated the expression of integrin α4β1. Thus, we hypothesis that HMGB1 regulation of iPS and PMN competitive with homing and infiltration in injuried tissue. Through lung ischemia-reperfusion induced acute lung injury after neutrophil depletion and microfluid chip model, using the technology of transgenic and RNAi, to demonstrate that HMGB1 regulate the iPS,PMN competitive homing and infiltration in the lung tissue.In depth to investigate the role of integrin α4β1 mediated HMGB1 regulation of iPS,PMN competitive homing and infiltration in the injured lung tissue. This study is to provide a potential new means for improving the effectiveness of iPS targeted therapy.

英文关键词： induced stem cell;neutrophil cell;acute lung injury;competitive homing;HMGB1