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NETS in thrombosis and inflammatory responses

Denisa D Wagner

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National Institutes of Health (NIH)
Upon neutrophil activation, peptidylarginine deiminase 4 (PAD4) may translocate to the nucleus to citrullinate histones. This decondenses chromatin which is released as neutrophil extracellular traps (NETs). NETs trap microbes but also promote inflammation. Relevant to this application, PAD4/NETs play an important role in pathological thrombosis and their formation can be stimulated by cancer. The central hypotheses of this proposal are: NETs are involved in the formation of a stable organized and vascularized thrombus and breaking up NETs is necessary for thrombolysis. Thrombosis promotes NET deposition in the adjacent vessel wall and in distant organs leading to post-thrombotic syndrome (PTS) and an increased systemic pro-coagulant and pro-inflammatory state. Finally, PAD4/NETs elevate coagulation in cancer and promote tumor angiogenesis and growth. To address the hypotheses, we will study several models of deep vein thrombosis (DVT) and breast cancer in wild-type (WT) and genetically engineered mice. The special knockouts to be used include PAD4-/- and newly generated DNase 1-/- mice. Novel technologies will be applied to extract 3D models of the neovasculature to generate vasometrics from the thrombi. Also, shear-activated nanotherapeutics (SA-NTs) will be tested to induce thrombolysis. The proposal has two specific aims: Aim1: to study NETs in venous thrombosis and thrombolysis. In this aim, we propose to investigate the role of NETs in various stages of DVT formation and in resulting fibrosis of the vessel wall. We will evaluate the role of extracellular chromatin and platelets in thrombus neo- vascularization and how chromatin and neovascularization affect thrombolysis. Aim 2: to study NETs/PAD4 in thrombosis-induced systemic inflammation and cancer-induced thrombosis. In this aim, we will examine what systemic effects and susceptibilities a mouse with DVT experiences and to what extent NETs contribute to pro-coagulant and pro-angiogenic activities of cancer. Thrombosis, including DVT/pulmonary embolism, is now the biggest killer in United States. We hope that our studies will broaden understanding of the roles NETs play in thrombosis and help to guide new treatments and prevention of pathological thrombosis, PTS and cancer-induced thrombosis.

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