Renal Oxygenation and Hemodynamics in Sepsis Associated Acute Kidney Injury

描述（由申请人提供）：在脓毒症的情况下，急性肾损伤（AKI）是经常观察到的，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对这种情况下肾功能衰竭的发病机制缺乏了解。该试点方案的具体目的是通过采用盲肠结扎和穿刺的啮齿动物模型，研究脓毒症相关AKI中导致肾脏缺氧的线粒体功能和形态学的原发性和/或继发性变化。该提案还旨在确定脓毒症背景下肾脏线粒体功能障碍和氧利用升高对整体肾功能和肾损伤的影响。研究策略是采用一种全面的调查方法来综合理解脓毒症相关AKI的发病机制。方法将包括生理技术，如全动物肾脏清除率，肾血流和微穿刺，分子技术，以评估线粒体生物能量，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，这些将在随后的独立资助提案中进一步深入研究。所获得的见解将是有价值的，超出了模型研究给予线粒体功能障碍的普遍含义。申请人的短期目标是在K08和O'Brien中心试点和可行性资助的支持下，获得R03试点资助，以建立迄今为止获得的有趣和新颖的结果，继续发展到有竞争力的R01应用的发展轨迹。长期目标是在肾脏生理学和病理生理学中，在肾脏血流动力学、氧合和线粒体功能的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.