PP2Cδ调控的线粒体ROS通路在肺损伤和炎症中的作用机制研究

Inflammation induced by infection and injury is considered to be one of the effective mechanisms to maintain the tissue homeostsis, while uncontrolled inflammatory responses can cause celluar injury and organ dysfunction. During the screening study on the molecules involved in the lung injury and inflammation, we found that loss of PP2Cδ (protein phosphatase 2C δ) rendered the mice more susceptible to the lung inflammation and injury induced by endotoxin or S. aureus. The in vitro study indicated that PP2Cδ-/- macrophages displayed enhanced activation and heightened inflammatory response, which appeared to associate with the modulation of mitochondrial ROS (mROS) signaling.This project is aimed to understand the action mode of PP2Cδ in regulating the pulmonary inflammatory signaling, as well as the interaction between PP2Cδ and mROS. Moreover, with loss-or-gain system, we will explore the effects of PP2C/mROS on the activaion, proliferation and apoptosis of inflammatory cells and pulmonary epithelial cells. Further endeavor is to establish the link between PP2C/mROS and the development of innate immunty, injury and inflammation in lung pathophysiology, which might extend our mechnistic understandng on the inflammatoy lung diseases.

针对感染和损伤因子发生的炎症反应是肺脏维持自稳的有效机制，但过强的炎症应答可引发细胞损伤和器官功能紊乱。在对参与肺损伤和炎症相关调控分子的筛选研究中，我们发现蛋白磷酸酶PP2Cδ(protein phosphatase 2C δ)分子的缺失可致小鼠由内毒素或金葡菌感染引发的肺部炎症增加，损伤加重。PP2Cδ缺失巨噬细胞表现为炎症反应增加，且该作用与线粒体ROS通路（mitochondrial reactive oxygen species, mROS）密切相关。本项目将进一步探究PP2Cδ参与肺部炎症信号通路的主要方式，阐明PP2Cδ与 mROS相互作用的分子机制；结合loss-or-gain手段分析PP2Cδ/mROS对炎性和肺上皮细胞活化、增殖、凋亡的影响；并通过基因敲除小鼠体系，建立该分子作用模式与肺部免疫-炎症-损伤之间的内在联系，从而为了解相关疾病的发生机理提供重要线索。

炎症性肺病和急性肺损伤是严重危害人类健康的临床常见疾病，人们对其发生机制目前仍未完全了解。本项目围绕肺部炎症和损伤中的信号调控这一关键科学问题展开研究，着重分析了蛋白磷酸酶PP2Cδ在肺部炎症和损伤发生过程中的表达规律和生物学意义，揭示了其对感染和损伤因子诱导的炎症信号转导、活化和转归等产生的影响；阐明了PP2Cδ对巨噬细胞线粒体代谢通路的调控作用及其机制；揭示了该分子通过调控ULK1自噬通路、CRL4b/c-cbl/RIG-I分子轴、以及WHSC1/Rictor/mTOC2通路促进免疫和炎症细胞表型和功能重编程机制；通过分子-细胞-动物整体水平的研究，进一步明确了PP2Cδ分子在肺损伤和炎症中的关键调控位点和作用机理，为深入理解“免疫-炎症-损伤”作用模式和炎症性肺病的发病机制提供新的重要线索。相关研究成果已发表论文7篇，其中影响因子超过5的SCI论文2篇，申请专利3项（已授权1项），培养研究生和青年教师7人。