NETS in thrombosis and inflammatory responses

NETS 在血栓形成和炎症反应中的作用

• 批准号: 8886274
• 负责人: DENISA D WAGNER
• 金额: $ 44.19万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-06-15 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8886274
• 关键词: Acute; Address; Affect; Alteplase; Binding; Blood Platelets; Blood Vessels; Cell Nucleus; Chromatin; Coagulants; Coagulation Process; Collaborations; DNA; Deep Vein Thrombosis; Defect; Deoxyribonucleases; Deposition; Distant; Event; Fibrosis; Genetically Engineered Mouse; Geometry; Goals; Histology; Histones; Infection; Inflammation; Inflammatory; Inflammatory Response; Injury; Institutes; Interleukin-6; Knock-out; Leukocyte Elastase; Leukocytes; Lung; Malignant Neoplasms; Mediating; Microbe; Modeling; Morphology; Mus; Neutrophil Activation; Nucleic Acids; Organ; Outcome; Plasma; Plasma Proteins; Play; Postphlebitic Syndrome; Predisposition; Prevention; Process; Protein-arginine deiminase; Proteins; Pulmonary Embolism; Role; Staging; Stroke; Study models; System; Testing; Thrombosis; Thrombus; Trees; Tumor Angiogenesis; Tumor Necrosis Factor-alpha; United States; Vascularization; Venous; Venous Thrombosis; Wild Type Mouse; Work; angiogenesis; density; experience; extracellular; improved; knockout animal; leukocyte activation; malignant breast neoplasm; nanotherapeutic; neovascularization; neovasculature; neutrophil; new technology; public health relevance; response; scaffold; three-dimensional modeling; thrombolysis; tumor; tumor growth; von Willebrand Factor

 DESCRIPTION (provided by applicant): 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.

 描述（由申请方提供）：中性粒细胞活化后，肽基精氨酸脱亚胺酶4（PAD 4）可转移至细胞核，使组蛋白瓜氨酸化。这使作为中性粒细胞胞外陷阱（NET）释放的染色质去致密化。NET捕获微生物，但也促进炎症。与该应用相关，PAD 4/NET在病理性血栓形成中起重要作用，并且它们的形成可以由癌症刺激。该建议的中心假设是：NET参与形成稳定的机化和血管化血栓，并且破坏NET是溶栓所必需的。血栓形成促进NET在邻近血管壁和远端器官中沉积，导致血栓形成后综合征（PTS）和全身促凝和促炎状态增加。最后，PAD 4/NETs提高癌症中的凝血并促进肿瘤血管生成和生长。为了解决这些假设，我们将在野生型（WT）和基因工程小鼠中研究几种深静脉血栓形成（DVT）和乳腺癌模型。待使用的特殊敲除包括PAD 4-/-和新产生的DNA酶1-/-小鼠。将应用新技术提取新生血管的3D模型，以从血栓生成血管测量。此外，将测试剪切激活纳米治疗剂（SA-NT）以诱导血栓溶解。该提案有两个具体目标：目标1：研究NET在静脉血栓形成和溶栓中的作用。在这个目标中，我们建议调查的作用，NET在DVT形成的各个阶段，并在导致纤维化的血管壁。我们将评估细胞外染色质和血小板在血栓新生血管形成中的作用，以及染色质和新生血管形成如何影响血栓溶解。目的2：研究NETs/PAD 4在血栓诱导的全身炎症和癌症诱导的血栓形成中的作用。在这个目标中，我们将研究什么样的全身效应和易感性与DVT的经验，以及在何种程度上NET有助于促凝血和促血管生成活性的癌症的小鼠。血栓形成，包括DVT/肺栓塞，现在是美国最大的杀手。我们希望我们的研究将扩大对NETs在血栓形成中作用的理解，并有助于指导新的治疗和预防病理性血栓形成，PTS和癌症诱导的血栓形成。