Renal Oxygenation and Mitochondrial Function in AKI

项目摘要 脓毒症背景下的急性肾损伤（阿基）是经常观察到的，并且是一个显著的并发症。 具有高发病率和死亡率的临床问题。其中一个主要障碍， 该领域的进展是缺乏对这种情况下阿基发病机制的理解。 本提案的具体目的是调查以下方面的主要和/或次要变化： 脓毒症相关阿基中线粒体功能和形态导致氧气不足 肾脏的利用。该提案还旨在确定线粒体的影响， 肾功能障碍和肾氧利用率升高对整体肾功能和肾脏 在败血症的情况下的损伤。 研究策略是采用综合调查方法， 了解脓毒症相关阿基的发病机制，使用临床相关盲肠 结扎和穿刺脓毒症模型。这些方法将包括生理技术， 作为整个动物肾清除率、肾血流量和微穿刺以及分子 评估线粒体生物能量学、ATP、活性氧生成和 电子显微镜以评估线粒体形态和动力学。这些调查 将提供重要的洞察血液动力学和非血液动力学因素， 脓毒症相关阿基的发病机制，并确定特定的机制途径和新的 治疗目标所获得的见解将是有价值的超越模型研究 鉴于线粒体功能障碍在肾脏疾病中的广泛影响。

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.