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

项目摘要 急性心肌梗塞，以及随后哺乳动物心脏恢复丧失的心脏组织的失败， 是世界范围内死亡的主要原因之一目前迫切需要开发一种治疗方法， 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 全球经济影响。斑马鱼（Danio rerio）具有强大的功能再生能力， 多种类型心室损伤后的心脏组织，包括冷冻损伤诱导的心脏细胞死亡。 在理解斑马鱼心脏再生过程方面取得了重大进展。为 例如，在心脏损伤后，剩余的心肌细胞被认为去分化，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 剩余的心肌细胞感知并响应损伤，包括转录因子调控网络如何 功能是引起肌节分解和心肌细胞去分化。 这项计划的目的是研究转录因子调控网络，其功能是促进 斑马鱼心脏再生已知转录因子基于以下调节染色质景观： 它们结合和募集染色质修饰酶到靶位点的能力。一级的重大变化 为了使成年心肌细胞对损伤做出反应并引发再生， 反应我的初步数据表明，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 心肌损伤与心肌细胞jun/fos表达的激活。此外，我的目标是确定 Jun/Fos在斑马鱼心脏再生中作用的分子机制 下游靶基因座和蛋白质相互作用伴侣介导染色质可及性的变化。最后， 我将确定JUN/FOS转录因子是否也在心脏保护过程中发挥类似的作用， Jun/Fos的过表达是否可以刺激成年小鼠模型的再生。的结果 本文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， 促进心脏再生的神经网络。了解这些分子机制， 对指导发展促进成年哺乳动物再生疗法的实际意义 心肌损伤后的心脏。

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.