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

• 批准号: 8824138
• 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
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8824138
• 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; 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; public health relevance; regional difference; research study; response; septic; vasoconstriction

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）：脓毒症中的急性肾损伤（AKI）经常被观察到，并且是一个具有高发病率和死亡率的重要临床问题。该领域进展的主要障碍之一是缺乏对这种情况下肾衰竭发病机制的了解。该试点提案的具体目的是使用盲肠结扎和穿刺的啮齿动物模型来研究脓毒症相关 AKI 中线粒体功能和形态的主要和/或继发性变化，这些变化会导致肾脏对氧气的利用效率低下。该提案还旨在确定脓毒症情况下线粒体功能障碍和肾脏氧利用率升高对整体肾功能和肾损伤的影响。研究策略是采用全面的研究方法来综合了解脓毒症相关 AKI 的发病机制。这些方法将包括生理技术，例如整个动物肾脏清除、肾血流和微穿刺，以及评估线粒体生物能、ATP 和活性氧生成的分子技术，以及评估线粒体形态和动力学的电子显微镜技术。这些研究将为脓毒症相关 AKI 发病机制中的血流动力学和非血流动力学因素提供重要见解，并确定特定的机制途径和新的治疗靶点，这些研究将在后续的独立资助提案中进一步详细探讨。考虑到线粒体功能障碍的普遍影响，所获得的见解将比研究的模型更有价值。申请人的短期目标是获得 R03 试点拨款，以在 K08 和奥布莱恩中心试点和可行性拨款的支持下迄今为止获得的有趣和新颖的结果为基础，以继续竞争性 R01 应用的进展轨迹。长期目标是在肾脏生理学和病理生理学中开发肾血流动力学、氧合和线粒体功能调节的独立专业领域。