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

项目摘要 2020年，约有160万美国人被确认患有炎症性肠病(IBD) 预计美国每年新诊断的IBD病例多达7万例。IBD 由影响胃肠道(GI)的慢性、复发性炎症性疾病组成，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，中性粒细胞不仅是 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，关于肽基精氨酸脱亚氨酶-4酶的粘膜保护作用的文献很少。 (PAD4)，其主要功能是促进瓜氨酸组蛋白3(H3Cit)的生成和 以中性粒细胞胞外陷阱(Net)的形式释放DNA。研究的总体目标是研究这一角色 PAD4在炎症性肠病中的作用这项建议旨在系统地阐明PAD4- IBD期间H3Cit和Net的介导释放。提出了三个具体目标，每个目标都进行了调查 PAD4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， 可独立实现，并将系统地表征：(I)Net在IBD小鼠模型中的作用， (2)PAD4缺乏在增强中性粒细胞颗粒蛋白的‘溢出’方面的不利后果和 (3)净网在防止细菌侵占粘膜方面的意义，否则这种侵占会永久化 肠道发炎。

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.