Renal Oxygenation and Mitochondrial Function in AKI

AKI 中的肾氧合和线粒体功能

基本信息

批准号：
9177677
负责人：
Prabhleen Singh
金额：
$ 34.88万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-18 至 2021-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9177677
关键词：
5&apos -AMP-activated protein kinase ATP Synthesis Pathway Accounting Acute Renal Failure with Renal Papillary Necrosis Address Animals Apoptosis Architecture Area Autophagocytosis Bioenergetics Biogenesis Cells Chimeric Proteins Clinical Critical Illness Data Development Electron Microscopy Embryo Fibroblasts Generations Generic Drugs Genetic Goals Hour Hypoxia Injury Injury to Kidney Investigation Kidney Kidney Diseases Lead Ligation Medical Metabolism Methods Micropuncture Mitochondria Modeling Molecular Morbidity - disease rate Morphology Mus Natural regeneration Nephrons Nephrotoxic Outcome Oxygen Oxygen Consumption Pathogenesis Pathway interactions Patients Peptides Phenotype Physiological Play Predisposition Production Proteins Puncture procedure Quality Control Reactive Oxygen Species Renal Blood Flow Renal Tissue Renal function Research Role Secondary to Sepsis Skeletal Muscle Sodium Staging Stress Study models Techniques Therapeutic Translating Tubular formation cell injury clinically relevant cost hemodynamics improved in vivo inhibitor/antagonist insight mitochondrial dysfunction mitochondrial metabolism mortality new therapeutic target novel outcome forecast regional difference renal tubular transport response sensor septic

项目摘要

PROJECT SUMMARY Acute kidney injury (AKI) in the setting of sepsis is frequently observed and is a significant clinical problem with high levels of morbidity and mortality. One of the major barriers to the progress in the field is the lack of understanding of the pathogenesis of AKI in this setting. The specific aims of this proposal is to investigate the primary and/or secondary changes in mitochondrial function and morphology in sepsis associated AKI that lead to inefficient oxygen utilization by the kidney. The proposal also aims to determine the effects of mitochondrial dysfunction and elevated oxygen utilization in the kidney on overall renal function and kidney injury in the setting of sepsis. The research strategy is to employ a comprehensive investigative approach for an integrative understanding of pathogenesis of sepsis associated AKI, using the clinically relevant cecal ligation and puncture model of sepsis. The methods will include physiological techniques such as whole animal kidney clearance, renal blood flow and micropuncture and molecular techniques to assess mitochondrial bioenergetics, ATP, reactive oxygen species generation and electron microscopy to assess mitochondrial morphology and dynamics. These investigations will provide important insights into hemodynamic and non-hemodynamic factors in the pathogenesis of sepsis-associated AKI and identify specific mechanistic pathways and novel therapeutic targets. The insights obtained will be will be valuable beyond the model studied given the wide-spread implications of mitochondrial dysfunction in kidney disease.

项目摘要经常观察到败血症的急性肾脏损伤（AKI）高水平发病率和死亡率的临床问题。的主要障碍之一该领域的进展是在这种情况下缺乏对AKI发病机理的理解。该提案的具体目的是调查主要和/或次要变化脓毒症相关的AKI的线粒体功能和形态，导致氧气效率低下肾脏利用。该提案还旨在确定线粒体的影响整体肾功能和肾脏的肾脏功能障碍和氧气利用率升高败血症的伤害。研究策略是采用全面的调查方法进行综合使用临床相关的盲肠了解败血症相关的AKI的发病机理败血症的结扎和穿刺模型。这些方法将包括这样的生理技术随着全动物肾脏的清除，肾脏血流和微孔和分子评估线粒体生物能学，ATP，活性氧的产生和电子显微镜评估线粒体形态和动力学。这些调查将提供对血液动力学和非女性动力学因素的重要见解败血症相关的AKI的发病机理，并识别特定的机械途径和新颖的途径治疗靶标。获得的见解将是有价值的鉴于线粒体功能障碍在肾脏疾病中的广泛影响。