COMP通过UPRmt调控心肌梗死后心肌纤维化机制研究

心肌成纤维细胞（CFs）持续活化是心肌梗死后心肌纤维化的关键事件，过度机械牵拉是CFs活化的核心驱动因素。线粒体未折叠蛋白反应（UPRmt）可修复线粒体并促进成纤维细胞活化。生物信息学分析显示COMP在心肌纤维化和心肌成纤维细胞活化等多个数据集中变化均最为显著；机械牵拉可激活驱动COMP转录的转录因子Sp1；预实验结果显示si-COMP抑制CFs活化、抑制UPRmt，而COMP结合的整合素β1可协同促进UPRmt。综上所述，我们提出以下科学问题：（1）COMP是否在心肌梗死后心肌纤维化中起重要作用；（2）COMP是否主要通过促进UPRmt调控心肌纤维化；（3）整合素β1是不是COMP调控URPmt的关系因素；（4）Sp1激活是不是机械牵拉上调心肌成纤维细胞COMP表达的核心机制。围绕科学问题，本项目着眼于COMP和UPRmt，将阐明它们在心肌纤维化中变化的原因和后果，为临床防治提供新靶点。

Continuous activation of cardiac fibroblasts (CFs) is a key event of cardiac post-infarction fibrosis, and excessive mechanical traction is the core driver of CFs activation.The mitochondrial unfolded protein response (UPRmt) repairs mitochondria and promotes fibroblast activation.Bioinformatics analysis shows that the expression of COMP has the most significant changes in multiple data sets about cardiac fibrosis and cardiac fibroblasts activation.Intriguingly,mechanical traction can activate transcription factor Sp1, which can drive transcription of COMP.Preliminary results showed that si-COMP inhibited CFs activation and UPRmt,and that the integrin Integ -β1 combined with COMP can promote UPRmt synergistically.We thus propose scientific problems: 1. Does COMP play a key role in cardiac post-infarction fibrosis? 2. Is UPRmt essential for COMP regulating cardiac fibrosis? 3. Is Integ-β1 essential for COMP regulating UPRmt? 4. Does mechanical traction promote COMP transcription by activating Sp1? To solve these problems, the current project aims to focus on COMP and UPRmt in CFs, demostrating the roles and mechanisms of them on cardiac post-infarction fibrosis,and to provide new targets for clinical therapy.