PROJECT SUMMARY/ABSTRACT Sepsis is a major cause of death and morbidity in both developing and industrialized societies. While great effort has been dedicated to the study of acute organ injury during sepsis, little is known about the mechanisms underlying the chronic morbidities faced by sepsis survivors. One such morbidity is septic neurocognitive dysfunction (also known as chronic septic encephalopathy), a common, severe illness characterized by the accelerated onset of dementia. Recently, the laboratories of Dr. Eric Schmidt (with extensive expertise in the study of sepsis and glycobiology) and Dr. Paco Herson (with extensive expertise in the study of brain injury) have partnered to establish a mouse model of septic neurocognitive dysfunction. This model has allowed the Schmidt and Herson laboratories to explore a novel hypothesis: that septic degradation of the systemic endothelial glycocalyx (a heparan sulfate (HS)-rich layer lining the vascular lumen) releases biologically-active, circulating HS fragments capable of penetrating the hippocampus and disrupting growth factor signaling pathways implicated in cognition. This newly-created collaboration will explore this hypothesis by performing ex vivo electrophysiological studies of living mouse hippocampi, in vivo mechanistic investigations of neurocognitive dysfunction in mouse survivors of endotoxemia or polymicrobial sepsis, and mass spectrometry studies of human plasma samples collected from a cohort of septic patients who underwent rigorous testing of neurocognitive function after sepsis resolution. This novel proposal, which departs from the “hyperinflammatory” dogma of septic organ injury, promises to identify a mechanistic pathway that is not only responsible for the development of septic neurocognitive dysfunction, but is amenable to therapeutic targeting even in established sepsis.