YAP and IRF2BP2 regulation of cardiomyocyte innate immune responses

YAP 和 IRF2BP2 对心肌细胞先天免疫反应的调节

• 批准号: 10367328
• 负责人: Zhiqiang Lin
• 金额: $ 64.1万
• 依托单位: MASONIC MEDICAL RESEARCH LABORATORY, INC
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-12-15 至 2026-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10367328
• 关键词: Acute myocardial infarction; Adult; Binding; Binding Proteins; Cardiac; Cardiac Myocytes; Cardiomyopathies; Cells; Cessation of life; ChIP-seq; Chronic; Complex; Data; Disease; Exposure to; Functional disorder; Genes; Genetic Transcription; Goals; Growth; Heart; Heart Diseases; Heart Injuries; Heart failure; Immune; Immune response; Immune signaling; In Situ; Inflammatory; Injury; Innate Immune Response; Innate Immune System; Interferon Regulatory Factor 2; Ischemia; Knock-in Mouse; Light; Lipopolysaccharides; MAP3K7 gene; Maintenance; Mediating; Methods; Modeling; Molecular; Mus; Myocardial; Myocardial Infarction; Myocardial Ischemia; Myocarditis; NF-kappa B; Pathogenesis; Pathologic; Pathway interactions; Pattern; Pattern recognition receptor; Phosphotransferases; Plant Roots; Process; Production; Proteins; Publishing; Reactive Oxygen Species; Regulation; Reperfusion Injury; Reperfusion Therapy; Reporting; Role; Signal Pathway; Signal Transduction; Stress; System; TLR4 gene; Testing; Yang; cardiac regeneration; cardiogenesis; cell type; clinical application; cytokine; efficacy testing; gain of function; genetic corepressor; heart function; in vitro activity; in vivo; innate immune pathways; innovation; loss of function; myocardial damage; nanoparticle; new therapeutic target; novel; novel therapeutic intervention; overexpression; pathogen; pathogenic bacteria; response; therapeutic target; tissue repair

Cardiomyocytes (CMs) are building blocks and function units of the heart, and their dysfunction or loss is the root of heart failure. Similar with other specialized innate immune cells, CMs have their own innate immune molecular machinery. Ischemic or non-ischemic pathological stress activates CM innate immune signaling pathways, which stimulate pro-inflammatory cytokine release and reactive oxygen species (ROS) production. These innate immune responses are beneficial for defending CMs against pathogen invasion and for tissue repair, but can also cause myocardial damage. The ultimate goal of this project is to define new molecular mechanisms that regulate CM innate immune responses, which will shed light on the pathogenesis of pathogen or non-pathogen related cardiomyopathy. Damage/danger-associated molecular patterns (DAMPs) initiate innate immune responses by binding to pattern recognition receptors, and one of the best-characterized signaling axis is TLR4/NF-kB pathway. The Hippo-YAP pathway is crucial for heart development and cardiac regeneration, and disturbances in Hippo-YAP have been implicated in a range of heart diseases. IRF2BP2 (interferon regulatory factor 2 binding protein 2) is a transcription co-factor little studied in the heart. We recently found that YAP regulates CM innate immune responses by blunting TLR4/NF-kB signaling, and that IRF2BP2 is crucial for restraining TLR4 expression in the heart. In this project, we will test the hypothesis that YAP and IRF2BP2 are suppressors of CM innate immune responses. We propose the following two aims. Aim 1. Define the role of YAP in CM innate immune responses. In this aim, we will determine whether YAP regulation of CM innate immune responses depends on its transcriptional activity. Additionally, we will develop a novel YAP modRNA delivery system. We previously showed that transiently activating YAP with intra-myocardial delivered aYAP modRNA reduced heart injury. However, the in situ delivery method limits aYAP modRNA's clinical application. Here, we will test the efficacy of CM targeted and nano-particle packaged aYAP modRNA in a murine cardiac ischemia/reperfusion model. Aim 2. Define the role of IRF2BP2 in CM innate immune responses. In this aim, we will perform IRF2BP2 gain- and loss-of-function studies to define its role in CM innate immune responses. Additionally, we will investigate the molecular mechanism of how IRF2BP2 regulates CM innate immune responses. Using the new Irf2bp2 knock-in mouse line we have recently generated, we will perform IRF2BP2 ChIP-Seq to identify its direct targets. This proposal is innovative and significant, as it focuses on dissecting the basic molecular mechanisms that underlie CMs innate immune responses, and it aims to develop new therapeutic strategies for reducing myocardial infarction injury.

心肌细胞(CM)是心脏的构件和功能单位，其功能障碍或缺失 是心力衰竭的根源。与其他专门的先天性免疫细胞类似，CMS有自己的 先天免疫分子机制。缺血性或非缺血性病理性应激激活CM 先天免疫信号通路，刺激促炎细胞因子的释放和反应 氧气(ROS)的产生。这些先天免疫反应有益于防御CMS。 抗病原体入侵和组织修复，但也可造成心肌损伤。终极的 该项目的目标是定义调节CM先天免疫的新的分子机制 反应，这将有助于阐明病原体或非病原体相关的发病机制 心肌病。损伤/危险相关分子模式(DAMP)启动先天免疫 通过与模式识别受体结合的反应，以及特征最好的信号轴之一 是TLR4/NF-kB途径。河马-YAP途径对心脏发育和心脏 河马的再生和紊乱与一系列心脏疾病有关。 IRF2BP2(干扰素调节因子2结合蛋白2)是目前研究较少的一种转录辅助因子。 心。我们最近发现，YAP通过钝化TLR4/NF-kB来调节CM的先天性免疫反应 IRF2BP2对抑制TLR4在心脏中的表达至关重要。在这个项目中，我们 将检验YAP和IRF2BP2是CM先天免疫反应抑制因子的假设。我们 提出以下两个目标。目的1.明确YAP在CM先天免疫反应中的作用。在这 目的：我们将确定YAP对CM先天性免疫反应的调节是否依赖于其 转录活性。此外，我们还将开发一种新型的YAP modRNA递送系统。我们 先前研究表明，心肌内瞬时激活YAP可传递aYAP modRNA 减少心脏损伤。然而，原位递送的方法限制了aYAP modRNA的临床应用。 在这里，我们将测试CM靶向和纳米颗粒包装的aYAP modRNA在小鼠体内的效果 心肌缺血/再灌流模型。目的2.明确IRF2BP2在CM先天免疫中的作用 回应。为此，我们将进行IRF2BP2功能增减研究，以确定其在 CM先天免疫反应。此外，我们还将研究分子机制如何 IRF2BP2调节CM的先天免疫反应。使用新的Irf2bp2敲入鼠标系列，我们 最近产生的，我们将执行IRF2BP2 CHIP-SEQ来识别其直接目标。这项建议 是创新的和有意义的，因为它专注于剖析基础的基本分子机制 CMS先天免疫反应，它的目标是开发新的治疗策略，以减少 心肌梗死损伤。