Nrf2 Protein Translation for Protection Against Tissue Injury

Nrf2 蛋白翻译可防止组织损伤

• 批准号: 9788495
• 负责人: QIN M CHEN
• 金额: $ 36.84万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-20 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9788495
• 关键词: 5' Untranslated Regions; Address; Affect; Angioplasty; Animal Model; Antioxidants; Autoantigens; Basic Science; Binding Proteins; Biological Markers; Blood; Cardiac; Cardiac Myocytes; Categories; Cell Death; Cell Membrane Permeability; Cell Survival; Cells; Chemicals; Clinical; Clinical Trials; Complex; Contracts; Coronary Artery Bypass; Coronary artery; Curcumin; Cytoprotection; Data; Development; Drug Metabolic Detoxication; Drug Prescriptions; Embryo; Emergency Situation; Event; Exhibits; Experimental Models; Fumarates; Genes; Heart Injuries; Heart failure; Human; In Vitro; Infarction; Injury; Intervention; Knockout Mice; Lead; Life; Literature; Maintenance; Mediating; Medical; Medicine; Membrane Proteins; Messenger RNA; Metabolism; Mitochondria; Mitochondrial Membrane Protein; Modeling; Mus; Myocardial; Myocardial Infarction; Myocardial Ischemia; Myocardium; NF-E2-related factor 2; Natural Products; Operative Surgical Procedures; Organ failure; Outer Mitochondrial Membrane; Oxidative Stress; PINK1 gene; PTEN-induced putative kinase; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Phase; Play; Postoperative Period; Preventive care; Procedures; Protein Biosynthesis; Protein Synthesis Inhibition; Proteins; Proteomics; RNA-Binding Proteins; Reperfusion Therapy; Reporting; Resolution; Ribosomal Proteins; Ribosomes; Risk; Role; Small Interfering RNA; Stress; Stress-Induced Protein; Sulforaphane; Testing; Therapeutic Index; Thioctic Acid; Time; Tissues; Toxicity Tests; Transgenic Animals; Transgenic Mice; Transgenic Organisms; Translating; Translations; Troponin; Work; Wound Healing; base; cardiogenesis; cinnamic aldehyde; effective therapy; induced pluripotent stem cell; mitochondrial membrane; mortality; novel; novel therapeutics; oltipraz; organ growth; overexpression; pre-clinical; preservation; protective effect; protein complex; recruit; response; ribosome profiling; success; transcription factor

Project Summary/Abstract: Myocardial infarction (MI) is an emergency state that requires immediate medical intervention. Coronary artery bypass graft (CABG) surgery or angioplasty procedures have becoming standard but effective treatment. Biomarkers of myocardial cell death are detected postoperatively in nearly all CABG patients or about 30% of angioplasty patients. Cell death remains detectable in the myocardium even when patients appear to have recovered from MI. The degree of cell death predicts the risk of developing heart failure and other complications. Identifying cytoprotective genes and uncovering their mechanisms of action pave the way for developing new therapies to reduce cardiac injury. Oxidative stress, as a result of ischemic or reperfusion and/or major surgery, usually causes an inhibition of protein synthesis. We found that Nrf2 mRNA can escape such general inhibition and be translated selectively. 5'UTR of Nrf2 mRNA was found to recruit La autoantigen for ribosomal association and de novo Nrf2 protein translation. Nrf2 is best known as a transcription factor for regulating the expression of antioxidant and detoxification genes. We have found that Nrf2 protects mitochondria from oxidative injury by physical association. We propose to utilize high resolution LC-MS/MS based proteomics, novel Nrf2 inducers in combination with transgenic animals, and in vitro and in vivo experimental models to test the hypothesis that elevated Nrf2 protein plays an important role in preservation of mitochondria and protection against myocardial injury. Aim 1 will investigate a novel pathway of Nrf2 induction by de novo Nrf2 protein translation. Components in the La and ribosomal protein complexes will be uncovered in an effort to understand the translational machinery under oxidative or ischemic stress in cardiomyocytes. Aim 2 will reveal a novel mechanism of Nrf2 mediated cytoprotection by testing Nrf2 participation in maintenance of mitochondrial integrity and metabolism. The domain of Nrf2 protein for physical interaction with mitochondria or mitochondrial outer membrane proteins will be identified for testing the significance in mitochondrial integrity, metabolism and mitophagy. Aim 3 will provide preclinical evidence for Nrf2 as the lead for cardiac protection. The importance of de novo Nrf2 protein translation for cardiac protection will be demonstrated using siRNA against La autoantigen. Contracting cardiomyocytes will be established for selection of Nrf2 inducers with suitable therapeutic indices. Mitochondrial preservation and cardiac protective effect of these compounds will be tested using Nrf2 overexpressing transgenics as a positive control. We have accumulated a large volume of data to support the success of the project. Accomplishment of the proposed work will not only provide needed answers to basic science questions, but also present the feasibility of a new category of drugs for cardiac protection.

项目摘要/摘要： 心肌梗塞（MI）是需要立即进行医疗干预的紧急状态。冠状动脉 旁路移植（CABG）手术或血管成形术已成为标准但有效的治疗方法。 术后几乎所有CABG患者术后检测到心肌细胞死亡的生物标志物，约占30％ 血管成形术患者。即使患者似乎患者似乎 从Mi恢复。细胞死亡的程度预示了发展心力衰竭和其他其他的风险 并发症。鉴定细胞保护基因并发现其作用机理为 开发新的疗法以减少心脏损伤。缺血或再灌注的结果 和/或大型手术，通常会导致蛋白质合成的抑制作用。我们发现NRF2 mRNA可以逃脱 这种一般的抑制作用和选择性地翻译。发现NRF2 mRNA的5'utr招募了la autoantigen 用于核糖体关联和从头nrf2蛋白翻译。 NRF2最著名的是 调节抗氧化剂和解毒基因的表达。我们发现NRF2保护 通过物理关联导致的氧化损伤的线粒体。我们建议利用高分辨率LC-MS/MS 基于蛋白质组学，新型的NRF2诱导剂与转基因动物结合，体外和体内 测试升高NRF2蛋白在保存中起重要作用的假设的实验模型 线粒体和防止心肌损伤的保护。 AIM 1将研究NRF2诱导的新途径 由NOVO NRF2蛋白翻译作者。 LA和核糖体蛋白质复合物中的成分将被发现 为了了解心肌细胞中氧化或缺血性应激下的翻译机制。 AIM 2将通过测试NRF2参与来揭示NRF2介导的细胞保护的新型机制 维持线粒体完整性和代谢。 NRF2蛋白的域，用于与 线粒体或线粒体外膜蛋白将被确定用于测试显着性 线粒体完整性，代谢和线粒体。 AIM 3将为NRF2提供临床前证据 用于心脏保护。从头NRF2蛋白翻译对心脏保护的重要性将是 使用siRNA针对La Autoantigen证明。将建立收缩的心肌细胞 选择具有合适治疗指数的NRF2诱导剂。线粒体保存和心脏保护性 这些化合物的效果将使用NRF2过表达的转基因作为阳性对照进行测试。我们有 积累了大量数据以支持项目的成功。拟议的成就 工作不仅将为基础科学问题提供所需的答案，而且还提出了新的可行性 用于心脏保护的药物类别。