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Novel mechanisms of redox signaling in acute kidney injury

急性肾损伤中氧化还原信号传导的新机制

基本信息

批准号：
10553732
负责人：
Anju Sreelatha
金额：
$ 14.9万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-02-01 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10553732
关键词：
Acute Renal Failure with Renal Papillary Necrosis Adenosine Monophosphate Amino Acids Antioxidants Bacteria Bacterial Model Biochemical Biochemistry Biological Assay Biological Models Biology Biotinylation Cell Death Cells Cellular biology Cisplatin Cytoprotection DNA Disease Drug Metabolic Detoxication Epithelial Cells Equilibrium Escherichia coli Eukaryota Family Functional disorder Gene Deletion Goals Health Homeostasis Human Injury to Kidney Ischemia K-Series Research Career Programs Kidney Kidney Diseases Knowledge Label Limb structure Lipids Mediating Mitochondria Mitochondrial Proteins Modeling Molecular Molecular Target Morphology Mus National Institute of Diabetes and Digestive and Kidney Diseases Nephrology Oxidants Oxidation-Reduction Oxidative Phosphorylation Oxidative Stress Pathology Pathway interactions Pattern Phenotype Phosphotransferases Physiological Physiology Positioning Attribute Post-Translational Protein Processing Process Production Prokaryotic Cells Protein Kinase Proteins Reactive Oxygen Species Regulation Renal function Reperfusion Therapy Research Rodent Rodent Model Role Saccharomyces cerevisiae Scientist Selenocysteine Signal Pathway Signal Transduction Signaling Molecule Source Stains System Technical Expertise Testing Therapeutic Thick Toxin Training Wild Type Mouse Work Yeast Model System analog biological adaptation to stress career cell type experimental study glutaredoxin inorganic phosphate kidney cell member mitochondrial dysfunction nephrotoxicity novel oxidation oxidative damage prevent renal epithelium selenoprotein skills therapeutic target

项目摘要

PROJECT SUMMARY Acute kidney injury resulting from ischemia reperfusion or toxin induced damage is correlated with mitochondrial dysfunction and increased ROS levels. The damaging effects of ROS on DNA, protein and lipids can be ameliorated by cellular antioxidants that detoxify the ROS. I have identified a novel mechanism of cellular detoxification in the mitochondria by a predicted pseudokinase, Selenoprotein O (SelO). Preliminary studies using E. coli and S. cerevisiae demonstrates that SelO catalyzes the transfer of AMP from ATP to multiple substrates involved in redox homeostasis to dampen oxidative damage and prevent cell death. Due to the phyletic spread and conservation from bacteria to humans, we postulate that SelO will play a role in oxidative stress response in mammalian systems that are heavily dependent on the mitochondria, such as the kidney. We will test this hypothesis by identifying the molecular targets and pathways mediated by SelO, and characterizing the functional importance of SelO in the rodent cisplatin-induced acute kidney injury model. A deep understanding and technical expertise in the fields of oxidative stress and nephrology are essential to the successful completion of this proposal. This career development award will allow me to strengthen my scientific skill set by training in kidney isolation, staining and phenotypic characterization in combination with biochemical assays to evaluate mitochondrial health. These studies will define a novel paradigm of signaling in the mitochondria, which can be usurped to identify therapeutic targets to prevent oxidative damage in a plethora of pathologies including acute kidney injury.

项目总结急性肾缺血再灌注损伤或毒素损伤与线粒体的关系功能障碍和ROS水平升高。ROS对DNA、蛋白质和血脂的破坏作用可能是通过细胞抗氧化剂使ROS解毒而得到改善。我发现了一种新的细胞学机制线粒体中的解毒作用是由一种预测的假激酶--硒蛋白O(SELO)实现的。初步研究利用大肠杆菌和酿酒酵母证明了Selo催化AMP从ATP转移到多个参与氧化还原动态平衡的底物，以抑制氧化损伤和防止细胞死亡。由于从细菌到人类的系统传播和保护，我们假设Selo将在氧化过程中发挥作用在严重依赖线粒体的哺乳动物系统中的应激反应，如肾脏。我们我将通过确定Selo介导的分子靶点和途径，并表征 SELO在顺铂致大鼠急性肾损伤模型中的作用一片深渊在氧化应激和肾脏病领域的理解和技术专长对于成功地完成了这项提案。这个职业发展奖将让我加强我的科学研究通过培训掌握肾脏分离、染色和表型鉴定与生化相结合的技能检测以评估线粒体健康状况。这些研究将定义一种新的信号传递范式线粒体，它可以被篡夺来识别治疗靶点，以防止过多的病理包括急性肾损伤。