Transcriptional Control of Neonatal Heart Regeneration

项目摘要 心脏病仍然是世界范围内的头号死亡原因，由于受伤的成年人心脏无法 再生我们试图描绘的机制，管理发展，疾病和再生的， 并在此基础上恢复损伤、疾病和衰老期间的心脏功能。相比之下 对于缺乏再生能力的成年哺乳动物心脏，新生儿心脏可以有效地再生 严重受伤后。为了探索新生儿心脏再生的分子基础，我们 分析了新生小鼠再生过程中基因表达和表观基因组的总体变化 与不能再生的晚期心脏相比。我们还进行了单细胞RNA 来自新生儿再生和非心肌细胞的心肌细胞和主要非心肌细胞类型的测序 有或没有损伤的再生心脏。这些综合数据集的整合已经开始揭示出 心脏的“再生”染色质景观和这一过程的转录激活因子和抑制因子。 该项目的总体目标是在这一信息基础上阐明 控制新生儿心脏对损伤的反应，并利用这些机制促进成人心脏 再生和修复。通过关注再生转录回路和旁分泌信号 机制，我们打算设计新的策略来增强心肌细胞的增殖和存活， 血管生成和由心脏的各种细胞成分介导的其它再生过程。 最终，心脏再生的分子解码将为激活 内源性途径的心脏修复和促进新的战略，恢复功能的受伤， 衰老的心脏

Project Summary Abstract Heart disease remains the number one cause of death worldwide, due to the inability of the injured adult heart to regenerate. We seek to delineate the mechanisms that govern development, disease and regeneration of the heart and to build upon this knowledge to restore cardiac function during injury, disease and aging. In contrast to the adult mammalian heart, which lacks regenerative capacity, the neonatal heart can efficiently regenerate following severe injury. To explore the molecular underpinnings of neonatal cardiac regeneration, we have analyzed global changes in gene expression and the epigenome during regeneration of the neonatal mouse heart in comparison to later stage hearts that cannot regenerate. We have also performed single-cell RNA sequencing of cardiomyocytes and the major non-myocyte cell types from neonatal regenerative and non- regenerative hearts with or without injury. Integration of these comprehensive datasets has begun to reveal a “regenerative” chromatin landscape of the heart and the transcriptional activators and repressors of this process. The overarching goal of this project is to build upon this body of information to elucidate the mechanisms that control the responses of the neonatal heart to injury and to harness these mechanisms to promote adult cardiac regeneration and repair. By focusing on regenerative transcriptional circuitry and paracrine signaling mechanisms, we intend to devise new strategies to enhance cardiomyocyte proliferation and survival, angiogenesis and other regenerative processes mediated by various cellular constituents of the heart. Ultimately, the molecular decoding of cardiac regeneration will provide a molecular blueprint for activating endogenous pathways for cardiac repair and facilitate new strategies for restoring function to the injured and aging heart.