心脏损伤后血管再生修复的调控机制及干预

本项目以组织器官再生修复过程中相关细胞属性的动态演变及调控网络为研究切入点，拟研究心脏损伤再生修复过程中再生血管内皮细胞属性演变及血管再生的动态时空调控网络和机制。我们发现小鼠心尖切除后心脏修复过程中心内膜内皮细胞可转变成动脉内皮细胞，且高表达前蛋白转化酶PCSK5。小鼠心脏过表达PCSK5减少心肌梗死面积，改善心功能。但是PCSK5在血管再生修复中的作用尚不清楚。本课题拟将单细胞RNA测序与单细胞ATAC测序结合，解析心脏损伤再生修复过程中细胞的时空异质性和转录调控在不同细胞中的特异性；探究不同细胞间相互作用对心脏再生修复的影响；解析心脏损伤后调控血管再生的关键转录因子、分子网络和调控因子，明确心脏损伤再生修复过程中演变成动脉内皮细胞的属性及调控机制。在小鼠心肌梗死、心尖切除及人血管类器官模型上，研究PCSK5对血管再生修复和心脏功能的影响，为促进心脏损伤后血管再生修复提供新策略。

This project focuses on the dynamic evolution of cell properties and regulatory networks in the process of tissue and organ regeneration and repair. We attempt to investigate the dynamic spatiotemporal regulatory network and mechanism of vascular regeneration during the regeneration and repair of cardiac injury. We analyzed the heterogeneity of regenerating cells after apical resection in mice, and found that endocardial endothelial cells could transform into arterial endothelial cells during the repair of heart injury, and the transformed cells were highly expressed PCSK5. The PCSK5 gene promoter in endothelial cells was associated with open chromatin states. Overexpression of PCSK5 in heart significantly reduced the myocardial infarcted area and improved cardiac function in mice. However, the mechanism of spatiotemporal regulatory network and the role of PCSK5 in vascular regeneration and repair are still unclear. The aim of this study is to combine single cell RNA sequencing with single cell ATAC sequencing to analyze the temporal and spatial heterogeneity of cells and the specificity of transcriptional regulation in different cells during cardiac regeneration and repair, explore the effects of different cell interactions on cardiac regeneration and repair, and analyze key transcription factors, molecular networks and regulatory factors regulating cardiac and vascular regeneration after cardiac injury. We attempt to explore the properties of transforming into arterial endothelial cells and determine the regulation mechanism involved in it. We will investigate the effects of PCSK5 on vascular regeneration and cardiac function in mice with myocardial infarction, apical resection and human blood vessel organoids models. This study will provide a new strategy for promoting revascularization and repair after cardiac injury.