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.

项目概要 急性心肌梗塞以及随后哺乳动物心脏无法恢复丢失的心脏组织是 全球死亡的主要原因之一。迫切需要开发能够促进治疗的疗法 缺血后健康心脏组织的存活或再生，这将产生巨大的社会和影响 全球经济影响。斑马鱼（Danio rerio）具有强大的功能再生能力 多种类型的心室损伤后的心脏组织，包括冷冻损伤诱导的心肌细胞死亡。 在了解斑马鱼心脏再生过程方面取得了重大进展。为了 例如，心脏损伤后，剩余的心肌细胞被认为会去分化、分解 肌节结构，并增殖以补充丢失的心肌细胞。然而，目前尚不清楚这些如何 剩余的心肌细胞感知损伤并做出反应，包括转录因子调控网络如何 功能引起肌节分解和心肌细胞去分化。 该提案的目标是研究转录因子调控网络，其功能是促进 斑马鱼的心脏再生。已知转录因子可调节染色质景观 它们结合和招募染色质修饰酶到目标位点的能力。水平发生重大变化 为了使成年心肌细胞对损伤做出反应并引起再生，染色质可能必须发生 回复。我的初步数据表明 Jun/Fos 转录因子对心脏损伤有反应 协调心肌细胞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 心脏损伤和心肌细胞中 jun/fos 表达的激活。此外，我的目标是确定 通过直接阐明斑马鱼心脏再生过程中 Jun/Fos 作用的分子机制 介导染色质可及性变化的下游目标位点和蛋白质相互作用伙伴。最后， 我将确定 JUN/FOS 转录因子在心脏保护和心脏保护过程中是否也发挥类似的作用。 Jun/Fos 的过度表达是否可以刺激成年小鼠模型的再生。结果 这里提出的研究将为遗传和表观遗传调控提供更深入的机制见解 具有促进心脏再生功能的网络。了解这些分子机制有助于 对指导开发促进成年哺乳动物再生的疗法的实际意义 心肌损伤后的心脏。