The role of energy regulation in the epithelial cell response to sepsis and the origin of multiple organ dysfuntion

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PROJECT ABSTRACT Severe sepsis is a syndrome estimated to affect 750,000 people in the United States and about 19 million people worldwide every year. With a rising incidence, death rates exceeding 20% and causing significant mor- bidity in survivors, sepsis is considered today a public health problem. Despite that mortality has been consist- ently associated with increasing organ dysfunction, the mechanisms by which sepsis causes multiple organ dysfunction are not well understood, and hence therapy remains reactive rather than preventive, and non- specific. Recent evidence has challenged the previous understanding of sepsis-induced organ dysfunction as being due to decreased blood flow-induced cell death by showing for example that acute kidney injury (AKI) occurs in the setting of normal or increased renal blood flow; and that it is characterized not by acute tubular necrosis or apoptosis, but rather by patchy, heterogeneous areas of tubular epithelial cell (TEC) oxidative stress and energy depletion. This paucity of apoptosis and necrosis, and the recognition that metabolic re- sponses to inflammatory injury may not only limit cell death in the acute phase but also, re-program energy regulatory pathways to determine future responses of epithelial cells, suggests that exploration of these mech- anisms represents potential therapeutic opportunities. Accordingly, the goal of this proposal is to determine the mechanisms by which the epithelial cell re-programs metabolism to adapt to inflammatory injury, and to under- stand the impact of these modifications on cell and organ function, and cell survival. The proposed research plan will be developed using cell culture and animal models in the frame of two specific aims. Aim 1 will deter- mine the role of AMPK in regulating the glycolytic and adaptive phases of the TEC response to sepsis. Aim 2 will dissect the role of mitophagy as an energy conserving response to limit TEC oxidative stress and cell death This research program will be framed in the context of a career development plan that will be described in the following pages and that is supported on three fundamental domains: Mentoring, Coursework and Research. The development of this program in the unique environment provided by the University of Pittsburgh, will allow the principal investigator (PI) to complete key training necessary to transition to independence focused on 1. The design and development of translational model systems to study sepsis induced organ dysfunction; 2. The quantification of epithelial cell energy regulatory pathways (AMPK), energy utilization and turnover, and mito- chondrial quality control processes during sepsis; and 3. Basic fluorescence and intravital microscopy tech- niques for the assessment of pathophysiologic processes in the living animal. These experiments will set the stage for future work to characterize the specific pathways linking energy regulation to organ dysfunction, and harness the possibility of manipulating these pathways to develop diagnostic, preventive and therapeutic strat- egies in a R01-funded project. Ultimately, the execution of this career development plan will uniquely position the PI as a future leader in sepsis research to improve the care of the critically ill patient. .