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: 10551249
• 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 2023-03-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10551249
• 关键词: Age; Aging; Applications Grants; Biology; Cell Nucleus; Chromatin; Darkness; 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; Vascularization; Work; Writing; age related; aging population; 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助长疾病和衰老：关注NET 此R35 0 IA应用程序是基于两个最近资助的NHLBI RO 1的扩展 赠款“NETS在血栓形成和炎症反应中的作用”和“NETS及其 在与年龄相关的炎症性疾病中调节酶。”多年来，我们 进行了一项成功的研究项目，研究血栓形成和炎症。我们 目前的重点是新发现的中性粒细胞胞外陷阱（NETs）。后 中性粒细胞活化，肽基精氨酸脱亚胺酶4（PAD 4）易位至细胞核 瓜氨酸化组蛋白。这使染色质去致密化，其作为NET释放。网 捕捉微生物，但我们已经展示了NET的阴暗面，即，它们促进血栓形成， 炎症和年龄相关的心脏和肺纤维化。我们的核心假设 计划是：NET参与形成一个稳定的有组织的， 血管化血栓和破坏NETs是溶栓所必需的。 血栓形成促进NET在邻近血管壁中的沉积， 远端器官导致血栓后综合征和全身性 促凝血和促炎状态。老化促进NET的形成， NET反过来又使慢性炎性和血栓性疾病升级。我们认为 抑制NET的形成或破坏NET的过程， 对宿主有益。最后，我们假设调控NETosis的基因，如 如肽基精氨酸脱亚胺酶4（PAD 4），影响衰老。 “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 是它的高引用率。该实验室一直由一个以上的NHLBI赠款资助， 15年来，我也是输血生物学领域一家大型PPG的PI。但在 在最近一段艰难的筹资时期，我花了太多时间为我的项目争取支持， 组获得长期资助将使我有更多的时间进行指导，写作 评论和学院活动。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， 持续的支持将确保我们能够有效地进行这项现有的研究。

项目成果

The role of platelets in thrombus fibrosis and vessel wall remodeling after venous thrombosis.

• DOI: 10.1111/jth.15134
• 发表时间: 2021-03
• 期刊: Journal of thrombosis and haemostasis : JTH
• 作者: DeRoo E;Martinod K;Cherpokova D;Fuchs T;Cifuni S;Chu L;Staudinger C;Wagner DD
• 通讯作者: Wagner DD

Neutrophil stimulation with citrullinated histone H4 slows down calcium influx and reduces NET formation compared with native histone H4.

与天然组蛋白H4相比，用柠檬酸的组蛋白H4用瓜酮组蛋白H4刺激钙的流入并减少净形成。

• DOI: 10.1371/journal.pone.0251726
• 发表时间: 2021
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Shi L;Aymonnier K;Wagner DD
• 通讯作者: Wagner DD

Alleviation of arthritis through prevention of neutrophil extracellular traps by an orally available inhibitor of protein arginine deiminase 4.

• DOI: 10.1038/s41598-023-30246-2
• 发表时间: 2023-02-23
• 期刊: SCIENTIFIC REPORTS
• 影响因子: 4.6
• 作者: Gajendran, Chandru;Fukui, Shoichi;Sadhu, Naveen M.;Zainuddin, Mohammed;Rajagopal, Sridharan;Gosu, Ramachandraiah;Gutch, Sarah;Fukui, Saeko;Sheehy, Casey E.;Chu, Long;Vishwakarma, Santosh;Jeyaraj, D. A.;Hallur, Gurulingappa;Wagner, Denisa D.;Sivanandhan, Dhanalakshmi
• 通讯作者: Sivanandhan, Dhanalakshmi

The Prominent Role of Hematopoietic Peptidyl Arginine Deiminase 4 in Arthritis: Collagen- and Granulocyte Colony-Stimulating Factor-Induced Arthritis Model in C57BL/6 Mice.

• DOI: 10.1002/art.42093
• 发表时间: 2022-07
• 期刊: Arthritis & rheumatology (Hoboken, N.J.)

Anti-inflammatory protective effect of ADAMTS-13 in murine arthritis models.

• DOI: 10.1111/jth.15828
• 发表时间: 2022-10
• 期刊: JOURNAL OF THROMBOSIS AND HAEMOSTASIS
• 影响因子: 10.4
• 作者: Fukui, Shoichi;Gutch, Sarah;Fukui, Saeko;Chu, Long;Wagner, Denisa D.
• 通讯作者: Wagner, Denisa D.