Dissecting the cytoprotective role of NRF1 in heart regeneration and repair

项目摘要 心力衰竭是世界上主要的死亡原因。心力衰竭病理生理学的核心是 成年哺乳动物心脏损伤后不能再生。与成年小鼠相比， 心脏能够在各种类型的损伤后完全再生，为实现这一可能性提供了新的进展 心脏再生和修复的机制。以前，我们发现，核因子红细胞衍生 2-相关因子1（NFE 2L1，也称为NRF 1）在再生心肌细胞群体中高度表达 在新生小鼠心脏中。虽然NRF1并不直接促进心肌细胞增殖，但它赋予心肌细胞强的 在体外和体内应激条件下保护心肌细胞。最近的研究表明，NRF1 调节多种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 功能在很大程度上是未知的。该提案概述了一项全面计划，以进一步剖析生物和 NRF1在心肌细胞中的病理功能，以提供对保护机制的重要见解， 是心脏再生和压力适应的基础。 在这项研究计划中，Aim 1将确定NRF1如何保护新生心肌细胞。目标2将展示 NRF1在哺乳动物新生心脏再生中的作用目标3将揭示NRF1作为压力的作用 调节剂在成人心脏缺血性损伤后。在辅导阶段，目标1和2将在 著名分子生物学家埃里克·奥尔森博士的实验室，并将产生数据和小鼠敲除 在独立阶段继续调查的模式。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的专业知识，包括单核RNA测序，以研究 新生儿心脏再生（目标1和2）。这样的经验将补充我以前的培训， 一个重要的数据生成平台。这项研究要求我 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及其下游途径在调节心肌细胞的应激反应，在这一指导期间， 培训将导致建立一个独立的利基为我自己的学术生涯。总之，这 申请将为我提供必要的科学培训，指导和职业发展， 过渡到独立。最重要的是，通过完成 提出的目标将对心血管科学领域作出重大贡献。

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.