Fibrinogen is a multifunctional plasma protein that after conversion into fibrin contributes to hemostasis and other physiological and pathological processes through its interaction with different proteins and cell types. Among these processes is inflammation, which plays a pivotal role in the pathophysiology of cardiovascular diseases. Recruitment of leukocytes from the circulation to sites of inflammation is an integral part of the inflammatory response and transendothelial migration of leukocytes is a key step in such recruitment. Numerous data indicate that fibrinogen is involved in this process. According to the proposed hypotheses, fibrinogen or its degradation products induce leukocyte transmigration by bridging leukocytes to the endothelium through the interaction with the endothelial receptors ICAM-1 or VE-cadherin, respectively. We have recently discovered that fibrin N-domains interact with the VLDL receptor (VLDLR), another receptor on endothelial cells, and this interaction also promotes leukocyte transmigration. Based on this discovery and some preliminary data, we hypothesize that fibrin promotes transendothelial migration of leukocytes through its interaction with VLDLR and such fibrin-induced VLDLR-dependent leukocyte transmigration can be modulated by specific inhibitors targeting this interaction. The major goal of the present application is to test this hypothesis. This will be accomplished in the following specific aims.
The first aim i s to further prove that fibrin-VLDLR interaction promotes leukocyte transmigration by studying the effect of fibrin on this process.
The second aim i s to establish the molecular mechanism of this interaction by mapping the complementary binding sites using recombinant techniques and characterizing the interaction between them using biochemical and biophysical methods.
The third aim i s to develop novel specific inhibitors of this interaction based on knowledge obtained and test their anti-inflammatory properties and cardioprotective effect using in vivo mouse models. The proposed study will clarify the molecular mechanisms of fibrin-dependent inflammation and may result in novel therapeutics for treatment of inflammation-related cardiovascular diseases including myocardial ischemia-reperfusion injury.
Inflammatory mechanisms play a pivotal role in the pathophysiology of cardiovascular diseases. They involve various factors including fibrin(ogen), which promotes transendothelial migration of leukocytes and thereby inflammation. The proposed studies will establish the molecular mechanism of the recently discovered VLDL receptor-fibrin interaction that modulates fibrin-dependent leukocyte transmigration, identify novel inhibitors of this process, and test their anti-inflammatory properties and cardioprotective effect using animal models.
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