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

急性心肌梗死，以及随后哺乳动物心脏恢复失去的心脏组织的失败，是 是世界范围内主要的死亡原因之一。迫切需要开发一种治疗方法来促进 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 对全球的经济影响。斑马鱼(Danio Rerio)具有强大的再生功能 多种类型的心室损伤后的心脏组织，包括冷冻损伤引起的心肌细胞死亡。 斑马鱼心脏再生过程的研究已取得重大进展。为 例如，在心脏损伤后，剩余的心肌细胞被认为是去分化、分解 肌节结构，并增殖以补充丢失的心肌细胞。然而，目前还不清楚这些因素是如何 剩余的心肌细胞对损伤的感知和反应，包括转录因子调控网络如何 诱导肌节解体和心肌细胞去分化的功能。 这项提议的目标是研究转录因子调控网络，它的功能是促进 斑马鱼的心脏再生。已知转录因子调节染色质景观的基础是 它们将染色质修饰酶结合并招募到靶基因的能力。水平上的重大变化 为了使成年心肌细胞对损伤做出反应并诱导再生，染色质可能必须发生。 回应。我的初步数据表明，Jun/Fos转录因子对心脏损伤和 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 下游靶基因座和调节染色质可及性变化的蛋白质相互作用伙伴。最后， 我将确定Jun/FOS转录因子是否在心脏保护和保护过程中也发挥类似的作用 过表达Jun/Fos是否能刺激成年小鼠模型的再生。评选结果 这里提出的研究将为遗传和表观遗传调控提供更深层次的机制洞察。 具有促进心脏再生功能的网络。对这些分子机制的了解 指导开发促进成年哺乳动物再生的治疗方法的实际意义 心肌损伤后的心脏。

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.