Transcriptional Control of Neonatal Heart Regeneration

新生儿心脏再生的转录控制

• 批准号: 10534778
• 负责人: RHONDA BASSEL-DUBY
• 金额: $ 56.5万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-12-06 至 2025-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10534778
• 关键词: Adult; Age; Aging; Cardiac; Cardiac Myocytes; Cause of Death; Chromatin; Data Set; Development; Disease; Epicardium; Gene Expression; Genes; Genetic Transcription; Global Change; Goals; Heart; Heart Diseases; Heart Injuries; In Vitro; Injury; Knowledge; Macrophage; Maps; Mediating; Molecular; Myocardium; Natural regeneration; Neonatal; Paracrine Communication; Pathway interactions; Play; Process; Proliferating; Regenerative capacity; Regenerative response; Testing; Time; Transcription Coactivator; Transcription Repressor; Transcriptional Regulation; angiogenesis; biological adaptation to stress; cardiac regeneration; cardiac repair; cell type; cytokine; endoplasmic reticulum stress; epigenome; functional restoration; heart function; improved; in vivo regeneration; injured; neonatal mice; regeneration function; regeneration potential; regenerative; response; severe injury; single-cell RNA sequencing; transcription factor

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.

项目概要 摘要 由于受伤的成人心脏丧失功能，心脏病仍然是全世界第一大死亡原因 我们试图描述控制发育、疾病和再生的机制。 相比之下，利用这些知识来恢复受伤、疾病和衰老期间的心脏功能。 相对于成年哺乳动物的心脏缺乏再生能力，新生儿的心脏可以有效地再生 为了探索新生儿心脏再生的分子基础，我们进行了研究。 分析了新生小鼠再生过程中基因表达和表观基因组的整体变化 我们还进行了单细胞 RNA 的研究。 对新生儿再生和非心肌细胞和主要非心肌细胞类型进行测序 这些综合数据集的整合已经开始揭示出有或没有损伤的再生心脏。 心脏的“再生”染色质景观以及该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些信息的基础上阐明其机制 控制新生儿心脏对损伤的反应，并利用这些机制来促进成人心脏 通过关注再生转录回路和旁分泌信号传导。 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为激活心脏提供分子蓝图 心脏修复的内源性途径，并促进恢复受伤者和患者功能的新策略 衰老的心脏。