Leveraging zebrafish models to dissect and enhance heart regeneration

利用斑马鱼模型解剖和增强心脏再生

• 批准号: 10163256
• 负责人: KENNETH D POSS
• 金额: $ 96.06万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-15 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10163256
• 关键词: Adult; American; Biological Models; Biology; Cardiac Myocytes; Cardiovascular system; Cicatrix; Excision; Gene Expression Regulation; Heart; Heart Ventricle; Heart failure; Human; Incidence; Injury; Laboratories; Mammals; Methods; Modeling; Molecular; Morbidity - disease rate; Myocardial Infarction; Myocardium; Natural regeneration; Principal Investigator; Regenerative response; Resolution; Tissues; United States; Viral Vector; Zebrafish; cardiac regeneration; healing; innovation; mortality; programs; regenerative; repaired; socioeconomics; teleost; tool

ABSTRACT The adult mammalian heart shows little or no significant innate regeneration of cardiac muscle after injury, and instead heals by scarring. This regenerative deficiency has major socioeconomic consequences, given that ischemic myocardial infarction is a leading cause of morbidity and mortality in the United States and over 5 million Americans suffer from heart failure. Many years ago, we found that the teleost zebrafish displays a vigorous regenerative response after partial resection of the cardiac ventricle, involving creation of new cardiomyocytes with little or no scarring. This discovery pioneered the model system approach to heart regeneration that is employed by many laboratories today. For the past 15 years, the principal investigator has introduced new tools and strategies to reveal many key concepts and mechanisms underlying heart regeneration in zebrafish. Here, we describe an integrative program that defines at new resolution the molecular components of innate heart regeneration, as well as mechanisms by which these components are regulated. We will harness this information to innovate new methods for controlling the efficacy of heart regeneration across species, including attempts to stimulate regeneration in mammals through factor delivery and gene regulation using viral vectors. The discoveries we make will continue to inform the fundamental biology of heart regeneration, and they will directly relate to ideas and methods to enhance regeneration and reduce the incidence of heart failure in humans. They are also likely to extend beyond cardiovascular biology and have relevance to the repair of other tissues.

抽象的 成年哺乳动物心脏损伤后很少或没有显着的心肌先天再生，并且 相反，通过疤痕愈合。这种再生缺陷具有重大的社会经济后果，因为 缺血性心肌梗死是美国发病率和死亡率的主要原因，超过 5 数百万美国人患有心力衰竭。许多年前，我们发现硬骨鱼斑马鱼表现出 部分切除心室后出现剧烈的再生反应，包括产生新的 心肌细胞几乎没有或没有疤痕。这一发现开创了心脏模型系统方法 当今许多实验室都采用再生技术。在过去的 15 年里，首席研究员 引入了新的工具和策略来揭示心脏的许多关键概念和机制 斑马鱼的再生。在这里，我们描述了一个综合程序，该程序以新的分辨率定义了 先天心脏再生的分子成分，以及这些成分的机制 受监管。我们将利用这些信息来创新控制心脏功效的新方法 跨物种再生，包括尝试通过因子传递刺激哺乳动物再生 和使用病毒载体的基因调控。我们的发现将继续为基础研究提供信息 心脏再生生物学，它们将直接涉及增强再生和心脏再生的想法和方法 降低人类心力衰竭的发生率。它们也可能扩展到心血管生物学之外 并与其他组织的修复相关。