转录因子Foxp1调控心肌增殖和血管新生参与心脏再生的作用与机制

出生时哺乳动物心肌具短暂再生能力，成年后心肌再生微弱不足以修复大面积心梗所致心肌损伤。Foxp1在胚胎期对心肌增殖具重要调控作用。预初结果显示心肌特异敲除Foxp1促进新生小鼠心肌再生。RNA测序结果显示Foxp1缺失后细胞增殖相关基因CCND1/2、ERBB2以及血管新生相关因子HIF-1ɑ表达上调，提示Foxp1敲除后通过调控心肌增殖和血管新生促进心肌再生。本项目拟通过新生小鼠心尖切除模型，探究心肌特异性Foxp1在心肌再生中的作用，表达谱测序寻找下游靶基因，ChIP和启动子报告系统证实Foxp1是否直接调控这些基因，并探寻具体分子机制。利用成体小鼠心梗模型探究Foxp1是否通过上述分子机制参与成体心脏损伤后再生。构建心肌特异启动子下Foxp1干扰的腺相关病毒载体心肌内注射，证实其在心肌损伤后再生作用，探索在体细胞靶向性基因调控策略在心脏再生中的作用。

The neonatal cardiomyocytes proliferation is sufficient to repair cardiac injuries; however, this ability is greatly diminished shortly after birth. Adult mammalian cardiomyocytes have limited proliferative capacity with poor ability to replace lost tissue after acute ischemic injury. Previous report showed that cardiac Foxp1 plays critical role in fetal myocardial proliferation. Our preliminary results show that cardiac specific Foxp1 know out enhances cardiomyocyte proliferation. RNA high-throughput sequencing reveals that cell proliferation related genes CCND1/2, ERBB2 and angiogenesis related factor HIF-1ɑ elevate after Foxp1 knock out, which suggests Foxp1 directly regulates cardiomyocytes proliferation as well as influences angiogenesis hence participate in cardiac regeneration. In this study, we seek to reveal the cellular and molecular mechanism of cardiac Foxp1 on cardiac regeneration by using neonatal mouse apex resection model. Then, we use adult mouse myocardial infraction model to confirm whether Foxp1 participate in the adult cardiac regeneration through the CCND1/2, ERBB2 and HIF-1ɑ pathway. Furthermore, an AAV9 virus vector expressing Foxp1 shRNA under the cardiomyocyte specific cTnT promoter will be tested in mouse myocardial infraction model by intercardial injection. This study will help to provide new strategy in treatment of cardiac injury by stimulating cardiac regeneration.