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.

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