放射性肺纤维化基质重构对Talin-Tiam1连接及负调节信号Rac1/SPRY2的影响

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中文摘要
肌成纤维细胞(MFB)凋亡抵抗、持续存在是放射性肺纤维化(RIPF)进行性发展的关键原因,但MFB发生凋亡抵抗的机制尚未明确。前期发现,RIPF特征性病理改变—基质重构可诱导MFB凋亡抵抗,其机制与减少SPRY2膜定位、PI3K-AKT通路活化有关。整合文献显示SPRY2膜定位活化对AKT具有负性调节作用,本项目在前期研究基础上提出假说:基质重构可能通过干扰Rac1活化而减少SPRY2膜定位,进而AKT脱抑制、MFB抵抗凋亡。拟采用力学分析技术结合去细胞基质,研究基质重构的异常力学信息是否引发机械能敏感蛋白Talin与Tiam1(Rac1活化因子)结合不良,导致Rac1未活化、SPRY2膜定位减少。本项目从基质重构这一新角度,开拓性探索基质重构力学信息向生化信号Rac1/SPRY2转接这一新颖过程,全新阐释MFB凋亡抵抗、RIPF进展的关键机制,并为控制RIPF提供新思路。
英文摘要
Apoptotic resistance of myofibroblasts (MFB) play key roles in the progression of radiation-induced pulmonary fibrosis (RIPF), yet the underlying mechanism remains unclear. Previous studies have found that matrix remodeling, the characteristic pathological changes of RIPF, induced MFB apoptosis resistance via the reduction of SPRY2 membrane localization and the activation of AKT. As membrane localization of SPRY2 acts as autonomous inhibitory factor on AKT, this project proposed that matrix remodeling may reduce SPRY2 membrane localization by interfering Rac1 activation, and then AKT de-inhibition and MFB resistance to apoptosis. This project will combined mechanical analysis technique with decellular matrix to explore whether the abnormal mechanical information of matrix remodeling triggers the unbinding of the mechanically sensitive protein Talin with Tiam1, resulting in the inactivation of Rac1 and the decrease of SPRY2 membrane localization. From the new perspective of matrix remodeling, this project explores the novel process of transferring matrix remodeling mechanical information to biochemical signal Rac1/SPRY2, and explains the new mechanism of MFB apoptosis resistance and RIPF progression, and may further provides new ideas for controlling RIPF.
期刊论文列表
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科研奖励列表
会议论文列表
专利列表
DOI:10.1016/j.bbrc.2020.04.023.
发表时间:2020
期刊:Biochemical and Biophysical Research Communications
影响因子:--
作者:郭凯宁;陈金燃;陈张杰;罗格莲;杨善民;张美;洪金省;张鲁榕;陈纯
通讯作者:陈纯
DOI:doi: 10.1016/j.intimp.2022.109179.
发表时间:2022
期刊:International Immunopharmacology
影响因子:5.6
作者:张彦伟;朱丽花;洪金省;陈纯
通讯作者:陈纯
DOI:10.1124/jpet.123.001695
发表时间:2024-05-01
期刊:JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
影响因子:3.5
作者:Zheng,Jianxing;Wu,Jiandong;Chen,Chun
通讯作者:Chen,Chun
雷公藤内酯醇通过抑制基质硬化、阻止肌成纤维细胞活化而缓解放射性肺纤维化
- 批准号:81473264
- 项目类别:面上项目
- 资助金额:60.0万元
- 批准年份:2014
- 负责人:陈纯
- 依托单位:
国内基金
海外基金
