Role of neutrophil extracellular traps (NETs) in Inflammatory bowel disease

项目摘要 2020年，约有160万美国人被证实患有炎症性肠病（IBD）。 并且预计在美国每年诊断出多达70，000例IBD新病例。IBD 包括影响胃肠道（GI）的慢性复发性炎性疾病，例如克罗恩病 疾病和溃疡性结肠炎。在参与IBD的各种免疫细胞中，嗜中性粒细胞不仅是IBD的免疫细胞， 第一反应细胞类型的炎症，但也参与限制炎症和促进伤口修复。 值得注意的是，缺乏关于肽基精氨酸脱亚胺酶-4的粘膜保护作用的文献 （PAD 4），其主要功能是促进瓜氨酸化组蛋白3（H3Cit）的生成， 作为中性粒细胞胞外陷阱（NET）释放DNA。本研究的总体目标是研究 炎症性肠病（IBD）中的PAD 4。本研究旨在系统地阐明PAD 4的作用。 在IBD期间介导H3Cit和NET的释放。提出了三个具体目标，每个目标都调查 PAD 4影响肠道健康和疾病的分子基础。这三个目标是相互关联的， 独立可实现的，并将系统地表征：（i）NET在IBD的鼠模型中的作用， (ii)PAD 4缺陷在增强中性粒细胞颗粒蛋白的“溢出”中的不利后果， (iii)NET在防止细菌侵入粘膜方面的重要性，否则可能使粘膜永久化 肠道炎症

Project Summary In 2020, approximately 1.6 million Americans were confirmed to have inflammatory bowel disease (IBD) and it is expected that as many as 70,000 new cases of IBD are diagnosed in the United States each year. IBD comprises of chronic, relapsing inflammatory disorders affecting the gastrointestinal (GI) tract, such as Crohn’s Disease and Ulcerative Colitis. Among various immune cells that participate in IBD, neutrophils are not only the first responder cell-type to inflammation, but also involved in limiting inflammation and facilitating wound repair. Of note, there is a dearth of literature on the mucoprotective role of the enzyme peptidyl arginine deiminase-4 (PAD4), whose predominant function is to facilitate the generation of citrullinated histone 3 (H3Cit) and the release of DNA as neutrophil extracellular traps (NETs). The overall goal of the research is to study the role PAD4 in inflammatory bowel disease (IBD). This proposal aims to systematically elucidate the role of PAD4- mediated release of H3Cit and NETs during IBD. Three specific aims are proposed, each of which investigates the molecular underpinnings by which PAD4 influence gut health and disease. The three aims are interrelated, independently achievable and would systematically characterize: (i) the role of NETs in murine models of IBD, (ii) the adverse consequence of PAD4-deficiency in potentiating the ‘spillover’ of neutrophil granule proteins and (iii) the significance of NETs in preventing bacterial encroachment on the mucosa, that otherwise can perpetuate intestinal inflammation.