Yvonne Nicolai (RA)
Jeniffer Retzlaff (Cand. med. StrucMed program)
Michael Klein (Cand. med.)
Janine Hauschild (Cand. med.)
Ramin Rokhazan (Cand. med., BMEP program)
Samir M Parikh MD (Harvard Medical School, Boston, MA, USA)
Paul van Slyke PhD & Dan Dumont PhD (Sunnybrooke, Toronto, Canada)
Gerard Pasterkamp MD & the FEM FATAL consortium (UMC Utrecht, NL)
Matjis van Meurs (UMC Groningen, NL)
Ingmar Lautenschlaeger MD (UKSH, Germany)
Christian Koenecke MD (Medical School Hannover, Germany)
Our group is interested in molecular mechanisms regulating endothelial barrier function in response to inflammation. We focus particularly on the Angiopoietin (Angpt) / Tie2 ligand receptor system which have been first described about a decade ago. Tie2 is a transmembrane receptor tyrosinekinase that is essential for embryonic vessel development. The Angpt/Tie system is critically important for the formation of blood and lymphatic vessels during embryogenesis, but in mature organisms its function shifts toward maintenance of endothelial homeostasis and reaction to insults. Angpt-1 is the major circulating Tie2 agonist, whereas Angpt-2 has antagonistic properties.
The major functional consequences of Angpt-1 driven Tie2 activation on mature vasculature are (Figure 1):
A) Endothelial survival and maintenance.
B) Endothelial barrier protection.
C) Anti-Inflammatory properties
Over the last years, we and others have hypothesized that activated endothelium releases pre-stored Angpt-2 that is then accessible for detection in the circulation. Consistent with this theory, septic individuals have higher levels of Angpt-2 than healthy controls. Those high Angpt-2 levels are associated with severity of illness and predict adverse outcome.
Besides its role as a disease biomarker we recently demonstrated in an Angpt-2 knockout mouse model that Angpt-2 directly contributes to multi-organ dysfunction and death in sepsis (Figure 2).
Based on these facts, we actively work on the exogenous modulation of the Tie2 activation states (i.e. phosphorylation) in murine experimental sepsis to establish a specific treatment strategy. In this regard, we could show that phosphorylation of Tie2 with a small peptide alone is sufficient to improve sepsis survival by over 40%. Our ultimate goal is to translate these experimental findings from bench to bedside to improve vascular dysfunction in septic patients.
Presently, we are also evaluating strategies that focus on excess Angpt-2 levels (via Angpt-2 depletion and function-blocking) to improve Tie2 phosphorylation status and thereby outcome in experimental sepsis.
Where to meet us: