The Role of PPARa in Cardiac Dysfunction in Sepsis

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Project Summary/Abstract Sepsis is a severe condition that often results in life-threatening multiorgan dysfunction. This proposal describes a 5-year research and training program that will permit Dr. Stephen Standage to develop as an independent investigator conducting clinically relevant, basic and translational research in sepsis pathogenesis. Having completed fellowship training in pediatric critical care medicine and building on a background of basic research training in sepsis immunology, the applicant seeks to develop new knowledge and skills to investigate how regulation of metabolic pathways influences organ dysfunction in sepsis with an objective to identify key mechanisms and therapeutic interventions that may improve patient outcomes. This research project specifically focuses on elucidating how PPARα influences cardiac energy production and heart function in sepsis. PPARα is a nuclear hormone receptor transcription factor that regulates many inflammatory and metabolic processes. Previous research has demonstrated that children with septic shock have significant downregulation of PPARα in peripheral blood leukocytes. The applicant's preliminary studies demonstrated that mice lacking PPARα (Ppara-/-) have much higher mortality in experimental sepsis, but reconstitution with bone marrow from wild type mice did not rescue the mortality phenotype, indicating a critical role for tissue PPARα in regulating organ injury and mortality in sepsis. Septic Ppara-/- mice have elevated plasma and tissue markers of severe cardiac injury and show decreased heart function compared to wild type mice, findings that are associated with lower fatty acid oxidation in the Ppara-/- group. Collectively, these data support the overall hypothesis that PPARα preserves cardiac function in sepsis by activating fatty acid oxidation and that augmenting cardiac PPARα signaling will improve survival. The specific aims of the proposed investigations are to: 1) Define the role of PPARα expression in heart function and survival in sepsis using a novel transgenic, cardiac-specific PPARα knock-out mouse and a mouse strain that over-expresses PPARα in the heart; 2) Identify the metabolic pathways that influence PPARα dependent cardiac function in the heart by measuring cardiac ATP production and substrate utilization, tissue gene expression and metabolite levels, and by evaluating mitochondrial structure and function; and 3) Determine whether pharmacologic PPARα activation ameliorates septic cardiac dysfunction and improves survival. This work is significant and has high translational potential because PPARα signaling is a targetable mechanism with FDA approved agonists already on the market. The hypotheses evaluated here challenge the prevailing paradigm that sepsis morbidity and mortality result from immune dysregulation and findings will have the potential to reframe the approach to treating this significant public health problem.