Elucidating the Molecular Mechanisms of Jun/Fos Transcription Factor Function in Cardiac Regeneration and Protection

阐明 Jun/Fos 转录因子在心脏再生和保护中功能的分子机制

• 批准号: 9760024
• 负责人: Arica Beisaw
• 金额: $ 5.53万
• 依托单位: MAX PLANCK INSTITUTE FOR HEART AND LUNG RESEARCH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9760024
• 关键词: ATAC-seq; Acute myocardial infarction; Address; Adult; Alleles; Area; Binding; Biological Models; Cardiac; Cardiac Myocytes; Cause of Death; Cell Cycle; Cell Death; Cell Survival; Cells; ChIP-seq; Chromatin; Cicatrix; Co-Immunoprecipitations; Coupled; Data; Developed Countries; Dominant-Negative Mutation; Drops; Embryonic Development; Enzymes; Epigenetic Process; Epitopes; Extracellular Matrix Proteins; Failure; Family member; Genetic; Genetic Models; Goals; Heart; Heart Injuries; Human; Immune; Inflammation; Injury; Innate Immune Response; Ischemia; JUN gene; Knowledge; Link; Mass Spectrum Analysis; Mediating; MicroRNAs; Modeling; Molecular; Mus; Myocardial; Myocardial Infarction; Myocardial Ischemia; Natural regeneration; Neonatal; Pathway interactions; Play; Process; Proliferating; Proteins; Rattus; Reporting; Resolution; Rodent; Role; Sarcomeres; Signal Pathway; Social Impacts; Structure; Testing; Tissues; Transgenic Mice; Up-Regulation; Ventricular; Zebrafish; base; cardiac regeneration; cardioprotection; economic impact; experimental study; functional outcomes; heart function; improved; injured; insight; jun Oncogene; macrophage; mouse model; neutrophil; novel; overexpression; postnatal; preconditioning; recruit; regenerative; repaired; response; therapy development; transcription factor

Project Summary Acute myocardial infarction, and subsequent failure of the mammalian heart to restore lost cardiac tissue, is one of the leading causes of death worldwide. There is an urgent need to develop therapies that facilitate survival or regeneration of healthy heart tissue after ischemia, which would have an enormous social and economic impact worldwide. The zebrafish (Danio rerio) possesses the robust ability to regenerate functional cardiac tissue after multiple types of ventricular injury, including induction of cardiac cell death by cryoinjury. Significant progress has been made in understanding the process of heart regeneration in zebrafish. For example, following cardiac injury, remaining cardiomyocytes are thought to dedifferentiate, disassemble sarcomeric structures, and proliferate to replenish lost cardiomyocytes. However, it remains unclear how these remaining cardiomyocytes sense and respond to injury, including how transcription factor regulatory networks function to elicit sarcomere disassembly and cardiomyocyte dedifferentiation. The goal of this proposal is to investigate the transcription factor regulatory networks that function to promote heart regeneration in zebrafish. Transcription factors are known to regulate the chromatin landscape based on their ability to bind and recruit chromatin-modifying enzymes to target loci. Significant changes on the level of chromatin must likely take place in order for adult cardiomyocytes to respond to injury and elicit a regeneration response. My preliminary data indicate that Jun/Fos transcription factors respond to cardiac injury and orchestrate downstream changes in the cardiomyocyte chromatin landscape to promote cardiac regeneration. The experiments proposed here aim to further understand the link between the innate immune response to cardiac injury and activation of jun/fos expression in cardiomyocytes. Furthermore, I aim to determine the molecular mechanisms of Jun/Fos action during zebrafish heart regeneration through elucidation of direct downstream target loci and protein interaction partners that mediate changes in chromatin accessibility. Lastly, I will determine whether JUN/FOS transcription factors also play a similar role during cardioprotection and whether overexpression of Jun/Fos can stimulate regeneration in an adult mouse model. The results of the studies proposed here will provide deeper mechanistic insight into the genetic and epigenetic regulatory networks that function to promote heart regeneration. Understanding these molecular mechanisms has practical implications for guiding the development of therapies to promote regeneration in the adult mammalian heart following myocardial injury.

项目摘要 急性心肌梗塞以及随后哺乳动物心脏恢复损失心脏组织的失败是 全球死亡的主要原因之一。迫切需要开发促进的疗法 缺血后健康心脏组织的生存或再生，这将具有巨大的社交和 全球经济影响。斑马鱼（Danio rerio）具有重生功能的强大能力 多种类型的心室损伤后的心脏组织，包括冷冻机诱导心脏细胞死亡。 在理解斑马鱼的心脏再生过程中取得了重大进展。为了 例如，在心脏损伤后，剩余的心肌细胞被认为可以去分化，拆卸 肉类结构，并扩散以补充损失的心肌细胞。但是，尚不清楚这些 剩余的心肌细胞感和对伤害的反应，包括转录因子调节网络 引起肌膜拆卸和心肌细胞去分化的功能。 该提案的目的是调查功能促进的转录因子调节网络 斑马鱼的心脏再生。已知转录因子基于 它们结合和募集染色质修饰酶与靶基因座的能力。关于水平的重大变化 染色质可能必须为成人心肌细胞做出反应并引起再生 回复。我的初步数据表明，JUN/FOS转录因子对心脏损伤和 编排心肌染色质景观的下游变化，以促进心脏再生。 这里提出的实验旨在进一步了解先天免疫反应与 心肌损伤和心肌细胞中JUN/FOS表达的激活。此外，我的目标是确定 通过阐明直接 下游目标基因座和蛋白质相互作用伙伴介导染色质可及性的变化。最后， 我将确定JUN/FOS转录因子在心脏保护过程中是否也起着相似的作用 JUN/FOS的过表达是否可以刺激成年小鼠模型中的再生。结果 此处提出的研究将为遗传和表观遗传调节提供更深入的机械洞察力 促进心脏再生的网络。了解这些分子机制 指导疗法发展以促进成人哺乳动物再生的实际意义 心肌受伤后的心脏。