Transcriptional Control of Neonatal Heart Regeneration

新生儿心脏再生的转录控制

• 批准号: 10365703
• 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/10365703
• 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; Mediating; Molecular; Myocardium; Natural regeneration; Neonatal; Paracrine Communication; Pathway interactions; Play; Process; 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; macrophage; 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.

项目摘要摘要 由于受伤的成人心脏无法 再生。我们试图描述控制发展，疾病和再生的机制 心脏并以这些知识为基础，以恢复受伤，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，新生儿心脏可以有效再生 严重受伤。为了探索新生儿心脏再生的分子基础，我们有 分析了新生小鼠再生期间基因表达和表观基因组的全球变化 与以后无法再生的心脏相比，心脏。我们还进行了单细胞RNA 从新生儿再生和非 - 有或没有受伤的再生心。这些全面数据集的集成已开始揭示 心脏的“再生”染色质景观以及此过程的转录激活剂和复制品。 该项目的总体目标是建立在这一信息的基础上，以阐明 控制新生儿对伤害的反应，并利用这些机制促进成人心脏 再生和维修。通过关注再生转录电路和旁分泌信号传导 机制，我们打算制定新的策略来增强心肌细胞的增殖和生存， 血管生成和其他由各种细胞构成心脏的再生过程。 最终，心脏再生的分子解码将提供一个分子蓝图，以激活 心脏修复和设施的内源性途径，以恢复受伤和 衰老的心。