We propose to continue our studies on the function of Weibel-Palade bodies (WPBs) and their major component, von Willebrand factor (VWF), in normal physiology, responses to injury and in disease models. The unifying hypothesis of this grant application is that WPB components, in particular VWF, play an important role both in thrombosis and inflammation and thus could modulate the extent of infarct produced by ischemic stroke. The project will consist of two interrelated Specific Aims: 1. New roles of VWF and its processing enzyme ADAMTS13 In this first aim, we propose to develop our recent observation that VWF and ADAMTS13 regulate leukocyte adhesion in vivo and examine its implications in important inflammatory processes such as wound healing and ischemia/reperfusion injury. The subaims are: a) Role for VWF and ADAMTS13 in leukocyte adhesion and recruitment in vivo, b) Role of VWF and ADAMTS13 in myocardial ischemia/reperfusion injury. 2. Role of WPBs and ADAMTS13 in stroke and stroke recovery Ischemia/reperfusion, such as occurs in ischemic stroke, induces WPB and VWF secretion. In this second aim, we propose to develop our preliminary observation that VWF deficiency decreases infarct formation after ischemic stroke and that ADAMTS13 plays a protective role after ischemia/reperfusion in the brain. Our hypothesis is that the reduction of VWF multimer size by ADAMTS13 has both anti-inflammatory and anti- thrombotic effects that together may reduce infarct volume after ischemic stroke. The subaims are: a) VWF and ADAMTS13 in stroke, b) Therapeutic effect of rADAMTS13 in ischemic stroke and comparison to tissue plasminogen activator (tPA). The application heavily relies on genetically modified mice, all available to our laboratory. The most important techniques will be an ischemic stroke model produced by transient middle cerebral artery occlusion and intravital microscopy. Both techniques are well established in our group. VWF and the other components of WPBs regulate inflammation and thrombosis and as such are key targets for drug development. Thus an exact understanding of their involvement in normal physiology and in disease models is essential. ADAMTS13, which down regulates VWF activity, has a significant therapeutic potential that we hope to delineate in this proposal.
We propose to study the function of molecules stored in Weibel-Palade bodies, vesicles within the cells of blood vessels. The contents of these vesicles are released during injury where the released molecules help in tissue repair. The Weibel-Palade bodies are also released in pathological situations and then they promote heart disease, inflammation and stroke. We will investigate how inhibition of a particular component of these vesicles could improve outcome in these major diseases.
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|Martinod, Kimberly; Wagner, Denisa D (2014) Thrombosis: tangled up in NETs. Blood 123:2768-76|
|Savchenko, Alexander S; Borissoff, Julian I; Martinod, Kimberly et al. (2014) VWF-mediated leukocyte recruitment with chromatin decondensation by PAD4 increases myocardial ischemia/reperfusion injury in mice. Blood 123:141-8|
|Martinod, Kimberly; Demers, Melanie; Fuchs, Tobias A et al. (2013) Neutrophil histone modification by peptidylarginine deiminase 4 is critical for deep vein thrombosis in mice. Proc Natl Acad Sci U S A 110:8674-9|
|Carbo, Carla; Yuki, Koichi; Demers, Melanie et al. (2013) Isoflurane inhibits neutrophil recruitment in the cutaneous Arthus reaction model. J Anesth 27:261-8|
|Suidan, Georgette L; Brill, Alexander; De Meyer, Simon F et al. (2013) Endothelial Von Willebrand factor promotes blood-brain barrier flexibility and provides protection from hypoxia and seizures in mice. Arterioscler Thromb Vasc Biol 33:2112-20|
|Brill, A; Suidan, G L; Wagner, D D (2013) Hypoxia, such as encountered at high altitude, promotes deep vein thrombosis in mice. J Thromb Haemost 11:1773-5|
|Duerschmied, Daniel; Suidan, Georgette L; Demers, Melanie et al. (2013) Platelet serotonin promotes the recruitment of neutrophils to sites of acute inflammation in mice. Blood 121:1008-15|
|Suidan, Georgette L; Duerschmied, Daniel; Dillon, Gregory M et al. (2013) Lack of tryptophan hydroxylase-1 in mice results in gait abnormalities. PLoS One 8:e59032|
|De Meyer, Simon F; Stoll, Guido; Wagner, Denisa D et al. (2012) von Willebrand factor: an emerging target in stroke therapy. Stroke 43:599-606|
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