Renal Oxygenation and Hemodynamics in Sepsis Associated Acute Kidney Injury

描述(由申请人提供)：脓毒症环境下的急性肾损伤(AKI)是一种常见的临床问题，具有很高的发病率和死亡率。在这一领域取得进展的主要障碍之一是对这种情况下肾功能衰竭的发病机制缺乏了解。这一试点方案的具体目的是利用盲肠结扎和穿孔的啮齿动物模型，研究脓毒症相关性AKI中线粒体功能和形态的原发和/或继发性变化，这些变化导致肾脏低效利用氧气。该提案还旨在确定在脓毒症背景下，肾脏线粒体功能障碍和氧气利用增加对整体肾功能和肾脏损伤的影响。研究策略是采用全面的研究方法，对脓毒症相关性急性KI的发病机制进行综合了解。这些方法将包括生理学技术，如全动物肾脏清除、肾血流和显微穿刺术，以及分子技术，以评估线粒体生物能量学、ATP和活性氧物种的产生，以及电子显微镜，以评估线粒体的形态和动力学。这些研究将对脓毒症相关AKI的发病机制中的血流动力学和非血流动力学因素提供重要的见解，并确定特定的机制途径和新的治疗靶点，这些将在随后的独立资金提案中进一步详细探讨。考虑到线粒体功能障碍的普遍含义，所获得的见解将比所研究的模型更有价值。申请者的短期目标是获得R03试点拨款，在K08和O‘Brien中心试点和可行性拨款的支持下，在迄今获得的有趣和新颖结果的基础上，继续推进R01的竞争性应用。长期目标是在肾脏生理学和病理生理学中的肾脏血流动力学、氧合和线粒体功能调节方面发展一个独立的专业领域。

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.