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

中性粒细胞胞外陷阱（NET）在炎症性肠病中的作用

• 批准号: 10608277
• 负责人: MATAM VIJAY-KUMAR
• 金额: $ 43.69万
• 依托单位: UNIVERSITY OF TOLEDO HEALTH SCI CAMPUS
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-15 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10608277
• 关键词: Acute; Address; Adhesions; Affect; Aggravated Colitis; American; Arginine; Arginine deiminase; Awareness; Biomass; CXCR4 gene; Cells; Charge; Chronic; Citrulline; Colitis; Crohn' s disease; Cytoplasmic Granules; DNA; Data; Deoxyribonuclease I; Disease; Elastases; Enzymes; Excision; Functional disorder; Gastrointestinal tract structure; Generations; Genetic; Goals; Histones; Homeostasis; Human; Immune; Immune response; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Intestinal Diseases; Intestines; Knowledge; LCN2 gene; Literature; Mediating; Mediator; Microbe; Modeling; Molecular; Mucositis; Mucous Membrane; Mus; Neutrophilia; Pathologic; Pathology; Pathway interactions; Peptide Hydrolases; Peroxidases; Phagocytes; Predisposition; Proteins; Reactive Oxygen Species; Recovery; Regulation; Relapse; Reporting; Research; Role; Sodium Dextran Sulfate; Structure; Therapeutic; Ulcerative Colitis; United States; adverse outcome; antagonist; antimicrobial; bactericide; cell type; clinically relevant; combat; disease diagnosis; extracellular; first responder; gastrointestinal; gut bacteria; gut health; gut inflammation; host microbiota; in vivo Model; interleukin-10 receptor; microbial; mouse model; neutrophil; opportunistic pathogen; pancreatic elastase II; pharmacologic; prevent; recruit; response; therapeutic target; translational applications; translational approach; wound healing

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.

项目概要 2020年，约160万美国人被确认患有炎症性肠病（IBD） 预计美国每年诊断出的 IBD 新病例多达 70,000 例。炎症性肠病 包括影响胃肠道 (GI) 的慢性、复发性炎症性疾病，例如克罗恩病 疾病和溃疡性结肠炎。在参与IBD的多种免疫细胞中，中性粒细胞不仅是 对炎症的第一反应细胞类型，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 (PAD4)，其主要功能是促进瓜氨酸组蛋白 3 (H3Cit) 和 DNA 作为中性粒细胞胞外陷阱 (NET) 释放。研究的总体目标是研究角色 PAD4 在炎症性肠病 (IBD) 中的作用。该提案旨在系统地阐明PAD4-的作用 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， 可独立实现并系统地表征：（i）NETs 在 IBD 小鼠模型中的作用， (ii) PAD4 缺陷增强中性粒细胞颗粒蛋白“溢出”的不利后果，以及 (iii) NETs 在防止细菌侵入粘膜方面的重要性，否则细菌会长期侵入粘膜 肠道炎症。