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.

炎症和血栓形成加剧心血管和肺部疾病：关注 中性粒细胞炎症性网状小体。 多年来，我们进行了一项成功的研究计划，研究血栓形成和 发炎。我们计划继续这方面的研究，目前重点放在中性粒细胞外。 陷阱(Net)和炎性小体在中性粒细胞和Net病中所起的作用。当中性粒细胞被激活时， 瓜氨酸氨基精氨酸脱亚胺酶4(PAD4)催化组蛋白并促进组蛋白所需的炎症体组装 有效的蚊虫感染和IL-β的产生。蚊帐捕获微生物，但我们已经展示了蚊帐的阴暗面，即它们 促进血栓形成、炎症和与年龄相关的心肺纤维化。我们的核心假设是 计划如下：Net参与稳定的、有组织的和有血管的血栓的形成 而打破网络是溶栓所必需的。血栓形成促进了Net在两个部位的沉积 邻近的血管壁和远处的器官，导致血栓后综合征和增加的全身性促血栓形成。 凝血和促炎状态。炎症，激活炎症小体和网络生成，如在 类风湿性关节炎有全身性后果，如发展为心力衰竭并保留射血 分数(HFpEF)。用NLRP3炎症体或PAD4抑制剂抑制小鼠炎症将减少 全身效应和缓解HFpEF的发展。我们进一步假设，在许多疾病中，抑制 净形成和减少血栓炎症对宿主是有利的。我们建议对这些进行测试 利用小鼠和人类血细胞、基因敲除小鼠和我们开发的小鼠疾病模型的假设。 瓦格纳实验室的工作被认为是创新和扎实的；一个客观的衡量标准是它的高引用率。 获得长期资助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，延长的支持期限将确保我们能够实现这一令人兴奋的目标 有效的研究计划。