Inflammation and thrombosis fuel cardiovascular and pulmonary disease: Focus on the interplay of neutrophil inflammasomes with NETs

炎症和血栓形成加剧心血管和肺部疾病：关注中性粒细胞炎症小体与 NET 的相互作用

• 批准号: 10572136
• 负责人: DENISA D WAGNER
• 金额: $ 123.9万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-15 至 2030-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10572136
• 关键词: Age; Aging; Applications Grants; Blood Cells; Cardiovascular Diseases; Cell Nucleus; Chronic; Darkness; Deposition; Development; Disease; Disease model; Distant; EFRAC; Event; Funding; Generations; Goals; Health; Heart; Heart failure; Histones; Human; Inflammasome; Inflammation; Inflammatory; Investigation; Knockout Mice; Leukocytes; Link; Lung diseases; Measures; Mentors; Microbe; Mus; Neutrophil Activation; Organ; Play; Postphlebitic Syndrome; Production; Protein-arginine deiminase; Pulmonary Fibrosis; Research; Rheumatoid Arthritis; Role; Side; Solid; Testing; Thinking; Thrombosis; Thrombus; Time; United States; Vascularization; Work; age related; aging population; chronic inflammatory disease; college; experimental study; extracellular; improved; inhibitor; innovation; neutrophil; preservation; prevent; programs; thromboinflammation; thrombolysis; thrombotic

Inflammation and thrombosis fuel cardiovascular and pulmonary disease: Focus on the interplay of neutrophil inflammasomes with NETs. For many years, we have conducted a successful research program studying the links between thrombosis and inflammation. We plan to continue this line of investigation with the current emphasis on neutrophil extracellular traps (NETs) and the role inflammasomes plays in neutrophils and NETosis. Upon neutrophil activation, peptidylarginine deiminase 4 (PAD4) citrullinates histones and promotes inflammasome assembly needed for effective NETosis and IL-beta production. NETs trap microbes but we have shown a dark side of NETs, i.e., they promote thrombosis, inflammation and age-related heart and lung fibrosis. The central hypotheses of our program are as follows: NETs are involved in the formation of a stable, organized, and vascularized thrombus and breaking up NETs is necessary for thrombolysis. Thrombosis promotes deposition of NETs in both the adjacent vessel wall and in distant organs, leading to post-thrombotic syndrome and an increased systemic pro- coagulant and pro-inflammatory state. Inflammation, activating inflammasome and NET generation as seen in rheumatoid arthritis has systemic consequences such as the development of heart failure with preserved ejection fraction (HFpEF). Inhibiting inflammation by NLRP3 inflammasome or PAD4 inhibitor in mice will reduce the systemic effects and alleviate HFpEF development. We hypothesize further that in many diseases, inhibition of NET formation and reduction of thromboinflammation would be beneficial to the host. We propose to test these hypotheses using mouse and human blood cells, knockout mice and murine disease models we have developed. The work by the “Wagner Lab” is considered innovative and solid; an objective measure is its high citation. Obtaining prolonged funding would free time for more mentoring, innovative thinking, and helpful collegiate activities. In addition, we now study chronic inflammatory and thrombotic diseases and their impact on aging. These experiments take time, and the extended duration of support would assure that we can pursue this exciting research program effectively.

炎症和血栓形成引发心血管和肺部疾病：关注 中性粒细胞炎性小体与NET。 多年来，我们已经成功地进行了一项研究计划，研究血栓形成与 炎症我们计划继续这条线的调查与目前的重点是中性粒细胞外 陷阱（NET）和炎性小体在中性粒细胞和NETosis中的作用。中性粒细胞激活后， 肽基精氨酸脱亚胺酶4（PAD 4）瓜氨酸化组蛋白并促进炎性小体组装， 有效NETosis和IL-β产生。NET捕获微生物，但我们已经展示了NET的阴暗面，即，他们 促进血栓形成、炎症和与年龄相关的心肺纤维化。我们的核心假设 程序如下：NET参与形成稳定的、有组织的和血管化的血栓 而破坏NETs是溶栓的必要条件。血栓形成促进NET在两个组织中的沉积， 邻近血管壁和远端器官中，导致血栓后综合征和全身促血栓形成增加。 凝血和促炎状态。炎症，激活炎性小体和NET生成，如在 类风湿性关节炎具有全身性后果，例如发生射血功能保留的心力衰竭， 分数（HFpEF）。在小鼠中通过NLRP 3炎性体或PAD 4抑制剂抑制炎症将降低小鼠的免疫应答。 全身效应和减轻HFpEF发展。我们进一步假设，在许多疾病中， NET形成和减少血栓炎症将对宿主有益。我们建议测试这些 使用小鼠和人的血细胞，敲除小鼠和鼠疾病模型，我们已经开发的假设。 “瓦格纳实验室”的工作被认为是创新和坚实的;一个客观的衡量标准是它的高引用。 获得长期的资金将腾出时间进行更多的指导，创新思维和有益的大学教育。 活动此外，我们现在研究慢性炎症和血栓性疾病及其对衰老的影响。 这些实验需要时间，而延长的支持时间将确保我们能够追求这一令人兴奋的目标。 有效的研究计划。