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.

Public Health Relevance

Sepsis is a common, severe condition caused by the body's response to an overwhelming infection. Sepsis survivors often face long-term problems with learning and memory. We are studying how small fragments of sugars, released from blood vessels damaged by sepsis, can interfere with brain processes necessary for learning.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM125095-03
Application #
9693739
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Dunsmore, Sarah
Project Start
2017-07-15
Project End
2021-05-31
Budget Start
2019-06-01
Budget End
2020-05-31
Support Year
3
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Colorado Denver
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045