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.

项目摘要缺血再灌注或毒素诱导损伤引起的急性肾脏损伤与线粒体有关功能障碍并增加ROS水平。 ROS对DNA，蛋白质和脂质的破坏作用可以是通过对ROS排毒的细胞抗氧化剂的改善。我已经确定了一种新型细胞机制通过预测的假子酶，硒蛋白O（Selo）在线粒体中排毒。初步研究使用大肠杆菌和酿酒酵母表明，Selo催化了AMP从ATP转移到多个涉及氧化还原稳态的底物可抑制氧化损伤并防止细胞死亡。由于我们假设Selo将在氧化中发挥作用哺乳动物系统中的压力反应在很大程度上取决于线粒体，例如肾脏。我们将通过识别Selo介导的分子靶标和途径来检验这一假设，并表征 Selo在啮齿动物顺铂诱导的急性肾损伤模型中的功能重要性。深处在氧化应激和肾脏科领域的理解和技术专长对成功完成了这一建议。这个职业发展奖将使我能够加强我的科学通过肾脏隔离，染色和表型表征与生化相结合的技巧评估线粒体健康的测定法。这些研究将定义一个新的信号范式线粒体，可以篡改以识别治疗靶标，以防止在很多人中氧化损伤病理包括急性肾脏损伤。