Pilot Project
PP3
Proteomic-based identification and validation of novel candidate mediators for damage and refurbishment of the endothelial glycocalyx in bacterial sepsis and COVID-19
Summary
The endothelial glycocalyx (eGC), a carbohydrate-rich layer lining the luminal surface of the endothelium, provides a first vasoprotective barrier against vascular leakage in sepsis. Using a proteomics approach in two cross-sectional cohorts of patients with either sepsis or COVID-19, we could identify several protein candidates associated with eGC damage in vivo. We plan to use our previously established Atomic-Force Microscopy-based endothelial cell culture system as a screening tool, to uncover causal relationships between candidates and eGC damage. Most promising candidates will be validated in vivo using intravital microscopy in the M.cremaster model in mice. In summary the project aims to discover new molecular targets to treat vascular barrier breakdown in sepsis.
Schematic overview of the work program: Screening of promising protein candidates is followed by further inhibitory and rescue treatments to uncover underlying signaling cascades. In case of promising results validation in murine sepsis model is planned.
Zwischenüberschrift
Our work program is hypothesis-driven. Our previous and preliminary data strongly imply that glycocalyx alterations play a crucial role in development of both sepsis and COVID-19 because data of glycocalyx (PBR) and microcirculation obtained in vivo strongly correlate with disease severity and mortality.
In this research project, we aim to:
- Identify proteins and corresponding signaling pathways in sepsis and COVID-19 with causal relation to glycocalyx alteration and discover strategies to protect and refurbish eGC decline.
- Furthermore, we plan to validate the results of promising candidates in an in vivo model of sepsis induced eGC damage.
