Mst1/2介导Spt4感染小鼠AECII再生和肺部炎症反应消退的双重机制研究

批准号:
81900004
项目类别:
青年科学基金项目
资助金额:
20.0 万元
负责人:
曹童童
依托单位:
学科分类:
H0102.呼吸系统感染、炎症与免疫
结题年份:
2022
批准年份:
2019
项目状态:
已结题
项目参与者:
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中文摘要
细菌性肺炎是儿童最常见的感染性疾病之一,抗生素的广泛使用已造成细菌耐药性增加,其治疗面临巨大挑战,如何提高肺自身的抗炎和修复能力是未来预防和治疗细菌性肺炎的重要举措。研究发现AECII密切参与损伤后肺泡上皮屏障重建和炎症反应消退,但具体机制不明。我们提出细菌感染后AECII中Mst1/2通过促进Yap/Taz入核,入核后的Yap/Taz作为转录共刺激因子,一方面能直接作用于AECII增殖分化基因,促进AECII的增殖分化以修复肺泡上皮屏障;另一方面能直接作用于IkB基因,促使炎症反应消退。在Spt4诱导的细菌性肺炎模型上证明Mst1/2抑制引起Yap/Taz入核减少,导致AECII增殖分化抑制和更严重的炎症反应。并通过CHIP证明Yap/Taz-Tead复合物能与IkBa基因结合。本研究为细菌性肺炎的屏障修复和肺部本身的抗炎效应提供新的机制,为从肺部自身对抗细菌性肺炎提供新的治疗靶点。
英文摘要
Bacterial pneumonia is one of the most common infectious diseases in children. The widespread use of antibiotics has led to an increase in the drug resistance of bacteria, and its treatment faces enormous challenges. How to improve the anti-inflammatory and repair ability of lung itself is an important measure to prevent and treat bacterial pneumonia in the future. It was found that AECII was closely involved in the reconstruction of alveolar epithelium barrier and the regression of inflammatory response after injury, but the mechanism was unknown. We suggest that Mst1/2 in AECII after bacterial infection can promote Yap/Taz entry and Yap/Taz as transcription costimulatory factor, on the one hand, it can directly act on the proliferation and differentiation gene of AECII and promote the proliferation and differentiation of AECII to repair the alveolar epithelial barrier. On the other hand, it can directly act on the IkB gene and promote the regression of inflammatory reaction. In the bacterial pneumonia model induced by Spt4, it was proved that the inhibition of Mst1/2 resulted in the decrease of Yap/Taz entry, the inhibition of proliferation and differentiation of AECII, and the more severe inflammatory reaction. It was proved by CHIP that Yap/Taz-Tead complex could bind to IkBa gene. This study provides a new mechanism for barrier repair of bacterial pneumonia and anti-inflammatory effects of the lung itself, and provides a new therapeutic target from the lung itself for the fight against bacterial pneumonia.
背景:细菌性肺炎是儿童最常见的感染性疾病之一,抗生素的广泛使用已造成细菌耐药性增加,其治疗面临巨大挑战。 NF-KB信号通路的激活是产生炎症反应的核心机制,如何有效抑制NF-KB信号通路的激活以及寻找靶向抑制该通路的关键环节是控制炎症反应的重要途径。.主要研究内容:即阐明炎症因子能诱导Mst1/2-Yap/Taz通路的激活,促进AECII的增殖分化。同时证实细菌性肺炎模型中Mst1/2出现显著激活,并进一步促进Yap/Taz入核,入核后的Yap/Taz作为转录共刺激因子激活IkB基因,IkB的激活使得NF-KB的活化受到抑制,从而产生抑制炎症反应的作用。另外,我们在筛选有效抗炎的药物过程中,发现我院的院内制剂银黛汤对NF-KB通路有较强的抑制作用,通过进一步探索,我们发现,银黛汤中的有效单体可以直接促进NF-KB的亚单位p65进行k48依赖的泛素化降解,从而起到抑制炎症反应的作用。.研究意义:本研究不仅证明了AECII中Mst1/2激活促进Yap/Taz入核后引起IkB活化,抑制NF-KB的激活,并且筛选出可以直接促进NF-KB的亚单位p65进行k48依赖的泛素化降解的有效单体成分,不仅为临床上治疗细菌性肺炎提供新的思路,而且为中药复方的抗炎效应提供证据,为进一步促进药物的临床转化奠定基础。
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