Nrf2 Protein Translation for Protection Against Tissue Injury

Nrf2 蛋白翻译可防止组织损伤

基本信息

批准号：
10238032
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
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-20 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10238032
关键词：
5&apos 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 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 base cardiogenesis cinnamic aldehyde effective therapy induced pluripotent stem cell mitochondrial membrane mortality myocardial injury novel novel therapeutics oltipraz organ growth overexpression oxidative damage pre-clinical preservation protective effect protein complex recruit response success tissue injury transcription factor wound healing

项目摘要

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) 是一种紧急状态，需要立即进行医疗干预。冠状动脉旁路移植术（CABG）手术或血管成形术已成为标准但有效的治疗方法。几乎所有 CABG 患者（约 30%）术后均可检测到心肌细胞死亡的生物标志物。血管成形术患者。即使患者似乎患有心脏病，心肌中的细胞死亡仍然可以检测到。从心肌梗死中恢复。细胞死亡的程度可以预测发生心力衰竭和其他疾病的风险并发症。识别细胞保护基因并揭示其作用机制为开发新疗法以减少心脏损伤。缺血或再灌注导致的氧化应激和/或大手术，通常会导致蛋白质合成的抑制。我们发现Nrf2 mRNA可以逃脱这种普遍的抑制并被选择性地翻译。 Nrf2 mRNA 5'UTR 被发现可募集 La 自身抗原用于核糖体关联和 Nrf2 蛋白从头翻译。 Nrf2 作为转录因子而闻名调节抗氧化和解毒基因的表达。我们发现 Nrf2 可以保护线粒体通过物理关联免受氧化损伤。我们建议使用高分辨率 LC-MS/MS 基于蛋白质组学，新型 Nrf2 诱导剂与转基因动物相结合，以及体外和体内实验模型检验 Nrf2 蛋白升高在保存中发挥重要作用的假设线粒体和防止心肌损伤。目标 1 将研究 Nrf2 诱导的新途径由 Nrf2 蛋白从头翻译。 La 和核糖体蛋白复合物中的成分将被揭示努力了解心肌细胞氧化或缺血应激下的转化机制。目标 2 将通过测试 Nrf2 参与来揭示 Nrf2 介导的细胞保护的新机制维持线粒体完整性和新陈代谢。 Nrf2 蛋白的物理相互作用域将鉴定线粒体或线粒体外膜蛋白以测试其重要性线粒体完整性、代谢和线粒体自噬。目标 3 将为 Nrf2 作为先导提供临床前证据用于心脏保护。 Nrf2 蛋白从头翻译对于心脏保护的重要性将是使用针对 La 自身抗原的 siRNA 进行了证明。收缩心肌细胞将被建立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将使用 Nrf2 过表达转基因作为阳性对照来测试这些化合物的效果。我们有积累了大量的数据支持项目的成功。拟议的完成情况这项工作不仅将为基本科学问题提供所需的答案，而且还将展示一种新方法的可行性心脏保护药物的类别。