Transcriptional Control of Neonatal Heart Regeneration

项目摘要摘要 心脏病仍然是全球头号死因，这是由于受伤的成年人心脏无力造成的。 重生。我们试图勾勒出管理人类发育、疾病和再生的机制 并在这一知识的基础上恢复受伤、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，新生心脏可以有效地再生 在严重受伤之后。为了探索新生儿心脏再生的分子基础，我们有 分析新生小鼠再生过程中基因表达和表观基因组的整体变化 心脏与不能再生的后期心脏相比。我们还进行了单细胞RNA 新生儿再生和非心肌细胞心肌细胞及主要非心肌细胞类型的序列分析 无论有没有受伤，都可以再生心脏。这些综合数据集的集成已经开始揭示出 心脏的“再生”染色质景观以及这一过程的转录激活和抑制因子。 这个项目的首要目标是在这些信息的基础上阐明 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， 由心脏的各种细胞成分介导的血管生成和其他再生过程。 最终，心脏再生的分子解码将提供激活的分子蓝图。 心脏修复的内源性途径，并促进新的战略，恢复受伤和 老化的心脏。

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.