Multi-organ omic model for sepsis therapeutic development

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ABSTRACT Sepsis-3 is defined as life-threatening organ dysfunction caused by the body’s dysregulated host response to an infection. An early feature of sepsis is the dysregulated activation of endothelial cells, which initiates a cascade of inflammatory signaling events by releasing various mediators, leading to leukocyte adhesion, migration, tissue damage and multiple organ dysfunction syndrome (MODS) if left uncontrolled. To date, therapeutic approaches for the treatment of sepsis are largely supportive, but there are no specific pharmacologic therapies available that protect from endothelial cell dysfunction. All sepsis drugs recently developed in rodents have failed in clinical trials, in large part because of the differences in species and the diverse phenotypes of endothelial cells demonstrating heterogeneity in function, morphology and omic expression patterns. Novel methods leveraging recent developments in omics are therefore needed to investigate how this heterogeneity impacts response to therapeutics in sepsis. In this project, I will employ omic and in silico models to investigate the role of specific protein targets in sepsis progression. Our group has identified Protein Kinase C-Delta (PKCδ) as a critical regulator of the inflammatory response, and I will use my model to determine the role of PKCδ in the progression of inflammatory signaling in human lung, liver and kidney endothelium in sepsis. Overall, these studies will help identify druggable/therapeutic targets that will then be experimentally validated using our novel microphysiological assay (MPA). I hypothesize that my proposed comprehensive, in silico proteomics model and corresponding validation experiments in our MPA will provide unique insight on the role of protein targets in predicting physiological responses in humans under septic and normal conditions. Our long-term goal is to develop a methodology to rationally design therapeutics for treating sepsis. The specific aims of my study are to 1) Create a comprehensive, in silico proteomics model to predict physiological responses in humans under septic and normal conditions and 2) Use a novel MPA to validate the role of the protein targets as predicted in Aim 1. These synergistic studies will focus on the role of the endothelial cell heterogeneity in sepsis, and the role of PKCδ and other protein targets in regulating the endothelial cell response in sepsis using an in silico model and an MPA employing human endothelial cells, and leukocytes and plasma from septic patients and healthy subjects to increase translatability in therapeutic development.