Dissecting the cytoprotective role of NRF1 in heart regeneration and repair

剖析 NRF1 在心脏再生和修复中的细胞保护作用

• 批准号: 10672388
• 负责人: Miao Cui
• 金额: $ 24.9万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10672388
• 关键词: Address; Adipose tissue; Adult; Affect; American; Antioxidants; Attenuated; Biological; Brain; Cardiac; Cardiac Myocytes; Cardiovascular Diseases; Cardiovascular system; Cause of Death; Cell Nucleus; Cellular Stress; Clinical; Complement; Complex; Cytoprotection; Data; Dedications; Developed Countries; Developing Countries; Disease; Endoplasmic Reticulum; Equilibrium; Erythroid; Functional disorder; Gene Delivery; Genes; Heart; Heart Diseases; Heart Injuries; Heart failure; In Vitro; Injury; Investigation; Knock-out; Knockout Mice; Laboratories; Liver; Measures; Mediating; Mentors; Modeling; Molecular; Mus; Myocardial Infarction; Myocardial Ischemia; Myocardial tissue; Myocardium; Natural regeneration; Neonatal; Newborn Infant; Nuclear; Oxidation-Reduction; Oxidative Stress; Pathologic; Pathology; Pathway interactions; Phase; Phenotype; Population; Positioning Attribute; Prevalence; Proliferating; Public Health; Recovery; Regenerative capacity; Regenerative response; Reperfusion Therapy; Research; Role; Science; Stress; Therapeutic; Tissues; Training; biological adaptation to stress; cardiac regeneration; cardiac repair; cardioprotection; cardiovascular disorder therapy; career; career development; design; disability; experience; experimental study; heart function; in vivo; in vivo regeneration; insight; ischemic injury; knock-down; multicatalytic endopeptidase complex; myocardial damage; neonatal mice; novel; overexpression; programs; proteostasis; regeneration following injury; regenerative; regenerative tissue; repaired; response; response to injury; restoration; single nucleus RNA-sequencing; symptom treatment; tissue repair; tool; transcription factor; transcriptome; transcriptomic profiling; treatment strategy

Project Summary Heart failure is the leading cause of death in the world. At the core of the pathophysiology of heart failure is the inability of the adult mammalian heart to regenerate following injury. In contrast to adults, the newborn mouse heart is capable of complete regeneration following various types of injury, providing a new inroad into possible mechanisms of cardiac regeneration and repair. Previously, we discovered that Nuclear Factor Erythroid-derived 2-related factor 1 (NFE2L1, also known as NRF1) is highly expressed in a regenerative cardiomyocyte population in neonatal mouse hearts. Although NRF1 does not directly promote cardiomyocyte proliferation, it confers strong protection to cardiomyocytes under stress conditions both in vitro and in vivo. Recent studies show that NRF1 regulates proteostasis and redox balance in multiple tissues in response to cellular stress, while its cardiac functions are largely unknown. This proposal outlines a comprehensive plan to further dissect the biological and pathological functions of NRF1 in cardiomyocytes to provide critical insight into the protective mechanism that underlies regeneration and stress adaptation in the heart. In this research plan, Aim 1 will establish how NRF1 protects neonatal cardiomyocytes. Aim 2 will demonstrate the function of NRF1 in mammalian neonatal heart regeneration. Aim 3 will uncover the role of NRF1 as a stress regulator in adult hearts following ischemic injury. In the mentored phase, Aims 1 and 2 will be carried out in the laboratory of the renowned molecular biologist Dr. Eric Olson, and will generate data and mouse knockout models for continued investigation in the independent phase. Aim 3 will be initiated during the K99 phase and continued during the independent phase, dedicated to investigating the therapeutic potential of NRF1 to treat adult ischemic heart disease. In order to gain research independence through mentored training, I will continue to develop expertise in applying transcriptome profiling, including single-nucleus RNA sequencing, to study neonatal heart regeneration (Aims 1 and 2). Such an experience will complement my prior training and constitute an important data generating platform throughout my career. The proposed research requires that I acquire additional mentoring in adult cardiac injury models and related cardiovascular phenotyping (Aim 3). Investigation of NRF1 and its downstream pathways in regulating the stress response of cardiomyocytes during this mentored training will lead to the establishment of an independent niche for my own academic career. In summary, this application will provide me with the scientific training, mentoring, and career development necessary as I transition to independence. Most importantly, the collective body of work generated through the completion of the proposed aims will make major contributions to the field of cardiovascular science.

项目概要 心力衰竭是世界上死亡的主要原因。心力衰竭病理生理学的核心是 成年哺乳动物心脏受伤后无法再生。与成年小鼠相比，新生小鼠 心脏能够在各种类型的损伤后完全再生，这为研究可能提供了新的途径 心脏再生和修复的机制。此前，我们发现核因子红细胞衍生 2 相关因子 1（NFE2L1，也称为 NRF1）在再生心肌细胞群中高表达 在新生小鼠心脏中。虽然NRF1不直接促进心肌细胞增殖，但它赋予心肌细胞强大的增殖作用。 在体外和体内应激条件下对心肌细胞的保护。最近的研究表明，NRF1 调节多个组织中的蛋白质稳态和氧化还原平衡以响应细胞应激，而其心脏 功能很大程度上是未知的。该提案概述了一项全面的计划，以进一步剖析生物和 NRF1 在心肌细胞中的病理功能为了解心肌细胞的保护机制提供了重要的见解 是心脏再生和压力适应的基础。 在该研究计划中，目标 1 将确定 NRF1 如何保护新生儿心肌细胞。目标 2 将展示 NRF1 在哺乳动物新生儿心脏再生中的功能。目标 3 将揭示 NRF1 作为压力的作用 缺血性损伤后成人心脏的调节器。在指导阶段，目标 1 和 2 将在 著名分子生物学家 Eric Olson 博士的实验室，将生成数据和小鼠敲除 独立阶段继续研究的模型。目标 3 将在 K99 阶段启动， 在独立阶段继续进行，致力于研究 NRF1 治疗的治疗潜力 成人缺血性心脏病。为了通过指导培训获得研究独立性，我将继续 发展应用转录组分析（包括单核 RNA 测序）的专业知识来研究 新生儿心脏再生（目标 1 和 2）。这样的经历将补充我之前的培训并构成 在我的职业生涯中一个重要的数据生成平台。拟议的研究要求我获得 对成人心脏损伤模型和相关心血管表型的额外指导（目标 3）。调查 NRF1及其下游通路在调节心肌细胞应激反应中的作用 培训将为我自己的学术生涯建立一个独立的利基。综上所述，这 应用程序将为我提供必要的科学培训、指导和职业发展 向独立过渡。最重要的是，通过完成以下工作而产生的集体工作 拟议的目标将为心血管科学领域做出重大贡献。