Translational approaches to unravel organ-specific microvascular endothelial responses in sepsis. PROGRAM SUMMARY: Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to an infection and is associated with high mortality. Systemic inflammation and endothelial activation with resultant microvascular leak, thromboses, and hypoxic tissue injury are hallmarks of sepsis. Yet, in over 100 trials, drugs aimed at modulating cascades of inflammation and coagulation have not proven to be efficacious. The primary reason for this failure is attributed to clinical and biological variability among critically ill patients. More recently, high-throughput approaches including gene-expression profiling have shown promise in disentangling patient- level heterogeneity in the host immune response. In contrast, sampling challenges coupled with cell and organ level heterogeneity have impeded a similar understanding of the host endothelial response. It follows that translational approaches that shed light on human microvascular pathobiology may lead to the discovery of targeted therapies that restore tissue homeostasis and shift sepsis care paradigms toward organ recovery. My research program seeks to address key knowledge gaps that currently impede scientific progress through projects spanning 3 domains. 1) DISCOVERY: The endothelium in patients remains inaccessible. Moreover, while endothelial heterogeneity and organ-specificity are increasingly recognized, their contribution to the evolution of organ dysfunctions remains poorly understood. To address this, we will enrich circulating endothelial cells from whole blood of children with septic shock with the primary objective of developing a transcriptomic atlas at single-cell resolution. By comparing signatures of circulating endothelial subsets from patients, relative to published datasets of tissue-resident endothelial cells, we will identify organ-specific targets for future hypotheses testi