How inflammation and thrombosis fuel disease and aging: Focus on NETs

炎症和血栓形成如何加剧疾病和衰老：关注 NET

• 批准号: 10327634
• 负责人: DENISA D WAGNER
• 金额: $ 88.5万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-11 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10327634
• 关键词: Age; Aging; Applications Grants; Biology; Blood Vessels; Cell Nucleus; Chromatin; Chronic; Deposition; Disease; Distant; Enzymes; Event; Funding; Genes; Goals; Grant; Health; Heart; Histones; Inflammation; Inflammatory; Inflammatory Response; Leukocytes; Longevity; Measures; Mentors; Microbe; Mus; National Heart, Lung, and Blood Institute; Neutrophil Activation; Organ; Postphlebitic Syndrome; Prevalence; Process; Protein-arginine deiminase; Pulmonary Fibrosis; Research; Secure; Side; Solid; Thrombosis; Thrombus; Time; Transfusion; United States; Work; Writing; age related; aging population; base; chronic inflammatory disease; college; experimental study; extracellular; improved; innovation; neutrophil; prevent; programs; thrombolysis; thrombotic

How inflammation and thrombosis fuel disease and aging: Focus on NETs This R35 0IA application is an extension based on two recently funded NHLBI RO1 grants entitled “NETS in thrombosis and inflammatory responses” and “NETs and their modulating enzymes in age-related inflammatory diseases.” For many years, we have conducted a successful research program studying thrombosis and inflammation. Our current emphasis is on newly discovered neutrophil extracellular traps (NETs). Upon neutrophil activation, peptidylarginine deiminase 4 (PAD4) translocates to the nucleus to citrullinate histones. This decondenses chromatin, which is released as NETs. 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: 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 the adjacent vessel wall and also in distant organs leading to post-thrombotic syndrome and an increased systemic pro-coagulant and pro-inflammatory state. Aging promotes NET formation and NETs in turn escalate chronic inflammatory and thrombotic diseases. We believe that inhibition of the process of NET formation or destruction of NETs would be beneficial to the host. Finally, we hypothesize that genes regulating NETosis, such as peptidylarginine deiminase 4 (PAD4), impact aging. The work by the “Wagner Lab” is considered innovative and solid; an objective measure is its high citation. The lab has always been funded by more than one NHLBI grant and for 15 years I was also the PI of a large PPG in Transfusion Biology. However, in the recent difficult funding period too much of my time was spent on securing support for my group. Obtaining prolonged funding would free my time for more mentoring, writing reviews, and collegiate activities. In addition, we now study chronic inflammatory diseases and their impact on aging. These experiments take time and the extended duration of support would assure that we could pursue this exiting research effectively.

炎症和血栓形成如何加剧疾病和衰老：关注 NET 此 R35 0IA 应用程序是基于最近资助的两个 NHLBI RO1 的扩展 题为“血栓形成和炎症反应中的 NETS”和“NETs 及其 调节与年龄相关的炎症疾病中的酶。”多年来，我们 进行了一项成功的研究计划，研究血栓形成和炎症。我们的 目前的重点是新发现的中性粒细胞胞外陷阱（NET）。之上 中性粒细胞激活，肽基精氨酸脱亚胺酶 4 (PAD4) 转位至细胞核 使组蛋白瓜氨酸化。这会解凝染色质，并以 NET 的形式释放。网络 捕获微生物，但我们已经展示了 NET 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。我们的中心假设 计划是： NET 参与形成稳定的组织和 血管化血栓和分解 NET 是溶栓所必需的。 血栓形成促进 NET 在邻近血管壁以及血管内的沉积 远处器官导致血栓后综合征和全身性炎症增加 促凝血和促炎状态。衰老促进 NET 的形成 NET 反过来又会加剧慢性炎症和血栓性疾病。我们相信 抑制 NET 形成或破坏的过程将是 对主人有利。最后，我们假设调节 NETosis 的基因，例如 肽基精氨酸脱亚胺酶 4 (PAD4) 会影响衰老。 “瓦格纳实验室”的工作被认为是创新且可靠的；客观衡量 就是它的高引用率。该实验室一直由不止一项 NHLBI 拨款资助，并且 15 年来，我一直是一家大型 PPG 输血生物学领域的 PI。然而，在 最近困难的融资时期我花了太多的时间来为我的项目争取支持 团体。获得长期资助可以让我腾出时间进行更多指导、写作 评论和大学活动。此外，我们现在研究慢性炎症 疾病及其对衰老的影响。这些实验需要时间和延长 支持的持续时间将确保我们能够有效地开展这项现有的研究。