线粒体质量控制保护心肌缺血再灌注损伤的机制研究

Mitochondria are the powerhouse of the heart and participate in multiple critical cellular activities. They have become the potential targets for treating myocardial ischemia-reperfusion injury. The applicant has previously elucidated the role of mitophagy and mitochondrial dynamism (fission and fusion) in normal hearts. Mitophagic mitochondrial removal underlies the metabolic transitioning of perinatal hearts (Science 2015). In adult mouse hearts, mitochondrial fission and fusion coordinately orchestrate mitophagic culling for the maintenance of mitochondrial quality and cardiac function (Cell Metab 2015, Circ Res 2015), whereas dysregulated mitochondrial quality control accelerates cardiomyocyte senescence and cellular dysfunction (Cell Metab 2017). On the basis of our previous findings, in this study we propose to establish mouse models with increased mitophagy or forced mitochondrial fission and evaluate whether they can improve mitochondrial quality and thus maintain cardiac function, providing protective effects against myocardial ischemia-reperfusion injury. Furthermore, we will make use of the in vitro ischemia-reperfusion model with H9C2 cells, perform high-throughput screening for small-molecule compounds that improve mitochondrial quality and verify their efficacy in vitro and in vivo against ischemia-reperfusion injury. Our research will determine whether and how mitochondrial quality control is implicated in the protection against myocardial ischemia-reperfusion injury and shed light on the discovery of new therapeutic interventions.

线粒体是心脏的主要能量来源并参与多项细胞活动，是治疗心肌缺血再灌注损伤的潜在靶点。申请人的前期研究阐明了线粒体自噬和动态（分裂和融合）在正常心脏中的作用。我们发现围产期心脏通过线粒体自噬转变代谢底物偏好（Science 2015），成年小鼠心脏中线粒体动态通过调控线粒体自噬，维持线粒体质量和心脏功能（Cell Metab 2015，Circ Res 2015），线粒体质量异常则导致心肌衰老和功能异常（Cell Metab 2017）。本项目在以往工作的基础上，拟分别构建促进线粒体自噬和促进线粒体分裂的小鼠模型，多层次地考察其在心肌缺血再灌注时是否能够提高线粒体质量、保护心脏功能。在此基础上，构建H9C2细胞体外模拟缺血再灌注模型，高通量地筛选提高线粒体质量的小分子化合物并进行体内验证。本项目的研究结果将为我们理解和利用线粒体质量控制在心肌缺血再灌注中的保护效应提供新的理论依据和转化前景。

线粒体是心脏的主要能量来源并参与多项细胞活动，是治疗心肌缺血再灌注损伤等心血管衰老及相关疾病的潜在靶点。项目负责人基于CRISPR基因编辑技术和体内外研究模型，合作建立了利用FOXO3遗传增强型人间充质细胞治疗心肌梗死的新策略；合作解析了4E-BP1、RICTOR、SIRT3、APOE等多种通过调控线粒体稳态和功能等途径，调节心血管衰老及相关疾病的新型分子机制；合作筛选并发现了氯喹、槲皮素等化合物，用于干预心血管衰老及相关疾病；此外，利用单细胞转录组学检测和分析手段，通过对不同年龄心脏组织的单核测序分析和对不同年龄心脏内皮细胞单细胞数据的深度分析，合作揭示了心血管衰老及老年群体心血管疾病易感性的细胞分子机制。基于上述成果，在Cell Research、Nucleic Acids Research、Nature Aging、Protein & Cell等杂志合作发表了11篇论文，合作申请了4项专利，其中1项获得授权。这些研究成果加深了我们理解线粒体稳态和功能在心肌缺血再灌注等心血管衰老及相关疾病的作用机制，为靶向线粒体调控心肌缺血再灌注等心血管衰老及相关疾病提供潜在靶点和干预手段。