The role of Pitx2 in heart injury and regeneration.

Pitx2 在心脏损伤和再生中的作用。

• 批准号: 9973601
• 负责人: Ge Tao
• 金额: $ 37.38万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9973601
• 关键词: Affect; Alleles; Antioxidants; Binding; Biology; Cardiac; Cardiac Myocytes; Cardiovascular system; Cell Cycle; Cell Nucleus; Cell Survival; Cells; Cessation of life; Cicatrix; Complex; Cytoplasm; Data; Deposition; Down-Regulation; Electron Transport; Equilibrium; Extracellular Matrix; Feedback; Fibroblasts; Fibrosis; Gene Expression; Genes; Genetic; Genetic Transcription; Goals; Heart; Heart Injuries; Heart failure; Homeostasis; In Vitro; Infarction; Injury; Left; Left ventricular structure; Modeling; Modernization; Mus; Myocardial; Myocardial Infarction; Myocardium; Myofibroblast; NF-E2-related factor 2; Natural regeneration; Nuclear Translocation; Operative Surgical Procedures; Oxidation-Reduction; Oxidative Stress; Pathway interactions; Primary Cell Cultures; Proteins; Reactive Oxygen Species; Reporting; Respiratory Chain; Role; Signal Transduction; Testing; Therapeutic; Tissues; Transgenic Mice; Ubiquitination; Ventricular; Ventricular Remodeling; Work; base; cardiac regeneration; cell injury; design; homeodomain; improved; migration; mouse model; nuclear factor-erythroid 2; overexpression; programs; regenerative; regenerative therapy; repaired; response to injury; single cell sequencing; transcription factor; transcriptome; ubiquitin-protein ligase

Project Summary This proposal describes a five-year program to investigate the roles of paired-like homeodomain 2 (Pitx2) signaling during cellular injury response and fibrotic scar formation after myocardial infarction (MI). MI accounts for millions of deaths worldwide annually. Therefore, developing an effective regenerative therapy is one of the major goals of modern cardiovascular biology. Pitx2, when overexpressed in cardiomyocytes, is capable of partially repairing myocardium in a mouse MI model. Pitx2 function is induced and promoted by the upstream nuclear factor erythroid 2 like 2 (Nrf2), a known regulator of redox balance. Unlike most of the regeneration- promoting factors that induce cell cycle reentry in cardiomyocytes, the Pitx2 signaling only has a mild effect on cardiomyocyte proliferation. Instead, Pitx2 regulates the expression of antioxidant scavengers and components of respiratory chain, both are critical for cell survival and homeostasis. Our Preliminary studies also suggest a role of Pitx2 in myofibroblast activity and fibrosis formation. Therefore, targeting Pitx2 for therapeutics provides alternative strategies which focus on cell survival and removing fibrosis. However, an in-depth study of Pitx2 is needed for designing an efficient targeting strategy. The Specific Aim 1 will test the hypothesis that overexpression of Pitx2 promotes the degradation of Nrf2 by inducing the expression of E3 ubiquitin-protein ligase Rbx1. This proposed negative feedback loop may promote the degradation of Nrf2, a key factor for the nuclear translocation and activity of Pitx2. We aim to explain why Pitx2 overexpression in myocardium can only partially repair the myocardium after MI. Transgenic mice with modified Pitx2 and/or Rbx1 expression will be subjected to MI to examine the hypothesis. We will also test an improved therapeutic strategy by overexpressing Pitx2 and Nrf2 simultaneously in infarcted cardiomyocytes. The Specific Aim 2 will focus on the downstream effects of Pitx2 signaling and test the hypothesis that Pitx2 activity in cardiomyocytes inhibits the transition of cardiac fibroblasts to myofibroblasts after MI. Preliminary data suggest that Pitx2 signaling in cardiomyocyte can affect myofibroblast activity. We proposed an interaction between cardiomyocytes and cardiac fibroblasts, coordinated by Pitx2, that can regulate fibrosis formation after MI. Mouse models with modified Pitx2 expression and in vitro primary cell cultures will be used to examine how cardiomyocyte-derived signaling can regulate fibroblast-to-myofibroblast transition, myofibroblast migration, and ECM deposition.

项目摘要 该提案描述了一个为期五年的计划，以调查成对的同源域2（PITX2）的作用 在心肌梗塞（MI）后，细胞损伤反应和纤维化疤痕形成过程中的信号传导。 MI帐户 每年在全球数百万人死亡。因此，开发有效的再生疗法是 现代心血管生物学的主要目标。 Pitx2在心肌细胞中过表达时， 在小鼠MI模型中部分修复心肌。 PITX2功能由上游诱导和促进 核因子红细胞2（如2（NRF2）），已知的氧化还原平衡调节剂。与大多数再生不同 - 促进诱导细胞周期重新进入心肌细胞的因素，PITX2信号仅对 心肌细胞增殖。相反，PITX2调节抗氧化剂清除剂和组件的表达 呼吸链对细胞存活和稳态至关重要。我们的初步研究也表明 PITX2在肌纤维细胞活性和纤维化形成中的作用。因此，针对治疗学的PITX2提供 着重于细胞存活和去除纤维化的替代策略。但是，对PITX2的深入研究是 设计有效的定位策略所需。具体目标1将检验以下假设 PITX2的过表达通过诱导E3泛素蛋白的表达来促进NRF2的降解 连接酶RBX1。该提出的负反馈回路可能会促进NRF2的降解，NRF2是该降解的关键因素 PITX2的核易位和活性。我们旨在解释为什么心肌中的Pitx2过表达只能 MI后部分修复心肌。具有改良的PITX2和/或RBX1表达的转基因小鼠将是 经过MI进行检查以检查假设。我们还将测试改进的治疗策略 在梗塞心肌细胞中同时表达PITX2和NRF2。具体目标2将重点放在 PITX2信号传导的下游效应，并检验了心肌细胞中的PITX2活性抑制的假设 MI之后，心脏成纤维细胞过渡到肌纤维细胞。初步数据表明PITX2信号传导 心肌细胞会影响肌纤维细胞活性。我们提出了心肌细胞与 由PITX2协调的心脏成纤维细胞可以调节MI后纤维化形成。带有鼠标模型 修饰的PITX2表达和体外原代细胞培养物将用于检查心肌细胞的衍生如何 信号传导可以调节成纤维细胞到肌纤维细胞过渡，肌纤维细胞迁移和ECM沉积。