Degradation of Neutrophil Extracellular Traps and .. (NET-LYSIS)
Degradation of Neutrophil Extracellular Traps and its impact on thrombolysis
Start date: Apr 1, 2014,
End date: Mar 31, 2016
Thrombosis is a major cause of morbidity and mortality emphasizing the need for new antithrombotic therapies.Recently, a novel pro-thrombotic mechanism was uncovered: Neutrophil Extracellular Traps (NETs). Neutrophils, the chief cells of the innate immunity, release DNA fibers during thrombosis. These extracellular DNA filaments form web-like structures known as NETs, which provide a scaffold and stimulus for thrombus formation in vitro and in vivo. Moreover, NETs are associated with thrombosis in patients underlining that NETs are a new therapeutic target.In order to identify therapies against NETs, we propose to address the unanswered question: how are NETs neutralized in vivo? It is known that extracellular DNA is digested by cooperative action of DNase1 and DNase1-like 3 (DNase1l3) in vitro. DNase1 and DNase1l3 are the only DNases in plasma and we hypothesize that they degrade NETs within thrombi. Furthermore, we speculate that degradation of NETs causes thrombus destabilization and facilitates thrombus resolution. To test the hypothesis, we will employ DNase1- and DNase1l3-deficient mice, infusions of recombinant murine DNase1 and DNase1l3 as well as infusions of DNase1 antibodies. To address NET degradation specifically, we will use genetically engineered mice, which cannot form NETs. Using these tools, we propose to investigate the role of plasma DNases in NET-degradation in murine models of arterial and venous thrombosis.If our hypothesis is correct, the proposed experiments will reveal the mechanism of NET-degradation in vivo and identify plasma DNases as drug candidates for antithrombotic therapy.
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