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The Role of the Mitochondrial UPR in Ischemic Protection

线粒体 UPR 在缺血保护中的作用

基本信息

批准号：
9223744
负责人：
Paul S Brookes
金额：
$ 61.85万
依托单位：
UNIVERSITY OF ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-01 至 2019-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9223744
关键词：
ATP-Binding Cassette Transporters Affect Animal Model Apoptotic Bioenergetics Biogenesis Biological Assay Bromides Caenorhabditis elegans Cardiac Cardiac Myocytes Cell Line Cell Nucleus Cell Survival Cells Chaperone Gene Complement Cytosol Data Disease Dominant-Negative Mutation Drug Metabolic Detoxication Electron Transport Employee Strikes Ethidium Generic Drugs Genes Genetic Genetic Models Glycolysis Heart Immunohistochemistry Injury Intervention Ion Transport Ischemia Laboratories Link Longevity Mammals Mediating Metabolic Metabolism Mitochondria Modeling Molecular Molecular Chaperones Monitor Mus Nuclear Organelles Orthologous Gene Oxygen Pathway interactions Peptide Hydrolases Peptides Pharmacology Physiological Play Predisposition Proteins RNA Interference Reagent Recovery Regulation Reperfusion Injury Reperfusion Therapy Research Resistance Resveratrol Reverse Transcriptase Polymerase Chain Reaction Role Signal Pathway Signal Transduction Signaling Protein Sirtuins Specificity Stress System Techniques Testing Transgenes Transgenic Organisms Translating Up-Regulation Work biological adaptation to stress common cellular transcription factor ATF coronary artery occlusion gain of function in vivo inhibitor/antagonist insulin signaling mitochondrial dysfunction mutant novel prevent protein misfolding proteostasis proteotoxicity public health relevance response trafficking transcription factor

项目摘要

DESCRIPTION (provided by applicant): Mitochondria are central to ischemia-reperfusion (IR) injury and protection. The mitochondrial unfolded protein response (UPRmt) is a signaling pathway that responds to mitochondrial dysfunction and proteotoxic stress. Our preliminary data suggests that the UPRmt protects against IR injury, consistent with up-regulation of mitochondrial chaperone genes, ROS detoxification machinery, and glycolytic capacity. In the genetic model organism C. elegans, the UPRmt's central mechanism of action has recently been described: mitochondrial proteotoxic stress regulates the matrix import and subsequent degradation of ATFS-1, a bZip transcription factor with dual targeting motifs. Under conditions of mild proteotoxic stress, matrix import is prevented through an ABC transport protein, HAF-1, acting in an undefined manner to suppress TIM/TOM activity. ATFS-1 instead traffics to the nucleus and activates a pro-survival repertoire of genes. Nuclear trafficking is both necessary and sufficient for protection, suggesting that the import of ATFS-1 into mitochondria provides a uniquely specific focal point for eliciting adaptation. This proposal aims to identify mechanisms through which the UPRmt protects C. elegans and to translate these findings to a mammalian cardiac model. Our approach will include defining mechanistic crosstalk with other signaling pathways that are also protective and will result in the identification of functional orthologs tha perform similarly in mammals as ATFS-1 and HAF-1.