Renal Oxygenation and Hemodynamics in Sepsis Associated Acute Kidney Injury

脓毒症相关急性肾损伤中的肾氧合和血流动力学

基本信息

批准号：
9027841
负责人：
Prabhleen Singh
金额：
$ 7.75万
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：
2015
资助国家：
美国
起止时间：
2015-07-01 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9027841
关键词：
ATP Synthesis Pathway Acute Renal Failure with Renal Papillary Necrosis Address Animals Area Autophagocytosis Bioenergetics Biogenesis C57BL/6 Mouse Cell Death Cell Survival Cellular Stress Cessation of life Clinical Critical Illness Data Distal Dynamin Electron Microscopy Electron Transport Energy Metabolism Etiology Functional disorder Funding Future Generations Generic Drugs Goals Grant Health Hypoxia Injury Injury to Kidney Investigation Kidney Kidney Failure Lead Ligation Mediating Medical Metabolism Methods Micropuncture Mitochondria Modeling Molecular Morbidity - disease rate Morphology Natural regeneration Nephrons Outcome Oxygen Oxygen Consumption Pathogenesis Pathway interactions Patients Peptides Physiological Physiology Puncture procedure Rattus Reactive Oxygen Species Recovery Regulation Renal Blood Flow Renal Tissue Renal function Research Rodent Model Role Secondary to Sepsis Sodium Staging Stress Study models Techniques Therapeutic Tissues Tubular formation base cell growth regulation cell injury cost hemodynamics hypoxia inducible factor 1 in vivo inhibitor/antagonist injured innovation insight interest mitochondrial dysfunction molecular marker mortality mouse model new therapeutic target novel outcome forecast prevent regional difference research study response septic vasoconstriction

项目摘要

DESCRIPTION (provided by applicant): 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 te pathogenesis of the renal failure in this setting. The specific aims of this pilot proposal is to investigate the primary and/or secondary changes in mitochondrial function and morphology in sepsis associated AKI that leads to inefficient oxygen utilization by the kidney using a rodent model of cecal ligation and puncture. 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. 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 and 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, which will be pursued in further details in a subsequent proposal for independent funding. The insights obtained will be will be valuable beyond the model studied given the universal implications of mitochondrial dysfunction. The short-term goal of the applicant is to obtain this R03 pilot grant to build upon the interesting and novel results obtained so far with the support of the K08 and O'Brien Center pilot and feasibility grant to continue the trajectory of progress to a competitive R01 application The long-term objective is to develop an independent area of expertise in the regulation of renal hemodynamics, oxygenation and mitochondrial function in renal physiology and pathophysiology.

描述（由申请人提供）：经常观察到败血症的急性肾脏损伤（AKI），并且是高水平发病率和死亡率的重大临床问题。该领域进步的主要障碍之一是在这种情况下缺乏对肾衰竭发病机理的理解。该试验提案的具体目的是研究脓毒症相关的AKI线粒体功能和形态的主要和/或次要变化，从而使用Cecal结扎和穿刺的啮齿动物模型，导致肾脏的氧气利用率无效。该提案还旨在确定肾脏中线粒体功能障碍和氧气利用率升高对败血症环境中总体肾功能和肾脏损伤的影响。该研究策略是采用一种全面的研究方法来整合对脓毒症相关的AKI的发病机理。这些方法将包括生理技术，例如全动物肾脏清除，肾脏血流，微题和分子技术，以评估线粒体生物能力，ATP和活性氧的产生和电子显微镜，以评估线粒体形态和动力学。这些研究将在败血症相关的AKI发病机理中对血液动力学和非母动力学因素提供重要的见解，并确定特定的机械途径和新型的治疗靶标，这将在随后的独立资金提案中进一步详细介绍。考虑到线粒体功能障碍的普遍含义，获得的见解将是有价值的。申请人的短期目标是获得这笔R03飞行员赠款，以基于迄今为止在K08和O'Brien Center Pilot的支持下获得的有趣和新颖的结果，以继续竞争性R01应用程序的进步轨迹，长期目标是长期目标是在肾脏血液模型和氧化统治方面的独立领域发展，并在肾脏血液中的专业知识中开发出独立的知识，并具有氧化能力的功能，并具有氧化型的功能。