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.
Acute kidney injury in the setting of sepsis is common in critically ill patients and is a significant medical problem with a poor prognosis. Lack of understanding of the mechanisms that lead to kidney injury has been a major barrier to progress in this area and improvement of outcomes in patients. This proposal aims to understand the mechanisms leading to kidney injury and has the potential to identify novel therapeutic targets for patients with sepsis associated kidney injury.
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