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：
8907809
负责人：
Paul S Brookes
金额：
$ 67.08万
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/8907809
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 Equilibrium Ethidium Exhibits 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 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 coronary artery occlusion gain of function in vivo inhibitor/antagonist insulin signaling mitochondrial dysfunction mutant novel prevent protein misfolding 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.

描述（通过应用程序提供）：线粒体是缺血 - 重新灌注（IR）伤害和保护的核心。线粒体展开的蛋白质反应（UPRMT）是一种信号通路，可应对线粒体功能障碍和保护性骨毒性应激。我们的初步数据表明，UPRMT可以防止IR损伤，这与线粒体伴侣基因，ROS ROS排毒机制和糖酵解能力的上调一致。在遗传模型组织中，最近描述了UPRMT的主要作用机理：线粒体蛋白毒性应激调节基质进口和随后的ATFS-1降解，ATFS-1是具有双靶标基序的BZIP转录因子。在轻度蛋白质应激的条件下，通过以不确定的方式作用以抑制TIM/TOM活性的ABC转运蛋白HAF-1可以防止基质进口。 ATFS-1取而代之的是传播到核并激活基因的临床曲目。核贩运既需要保护，又足以保护，这表明将ATFS-1进口到线粒体中为引起适应性提供了一个独特的特定焦点。该建议旨在确定UPRMT保护秀丽隐杆线虫并将这些发现转化为哺乳动物心脏模型的机制。我们的方法将包括与其他也受到保护的信号通路的定义机制，并将导致鉴定功能性直系同源物在哺乳动物中与ATFS-1和HAF-1相似。