The Role of Extracellular Histones and Neutrophil Extracellular traps in Necrotizing Enterocolitis

细胞外组蛋白和中性粒细胞细胞外陷阱在坏死性小肠结肠炎中的作用

基本信息

批准号：
9314723
负责人：
Hala Chaaban
金额：
$ 10.99万
依托单位：
UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-01 至 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9314723
关键词：
Ablation Acute Renal Failure with Renal Papillary Necrosis Address Animal Model Animals Antibodies Apoptotic Asphyxia Bacteria Biological Markers Blood Circulation Caring Cell Death Cells Cessation of life Complex DNA Data Diffuse Disease Disease Progression Emergency Situation Endotoxins Environment Escherichia coli Experimental Models Failure Functional disorder Gastrointestinal Diseases Genetic Histones Human Infant Infection Inflammation Inflammatory Infusion procedures Injury Intestines Ischemia Kinetics Klebsiella Infections Large Intestine Lead Measures Mediator of activation protein Medical Modeling Morbidity - disease rate Mus Necrosis Necrotizing Enterocolitis Neonatal Neutrophil Activation Neutrophil Infiltration Nuclear Nucleosomes Operative Surgical Procedures Organ Organ failure Outcome Paneth Cells Pathogenesis Pathologic Pathology Peptide Hydrolases Peroxidases Pharmacology Plasma Platelet Activation Play Premature Infant Prevalence Proteins Reperfusion Injury Reperfusion Therapy Role Sepsis Sepsis Syndrome Severity of illness Small Intestines Stimulus Thrombocytopenia Thrombosis Tissues Trauma base biomarker development clinical care cytokine extracellular feeding gastrointestinal genetic approach inhibitor/antagonist injured microorganism mortality mouse model neutrophil novel novel therapeutics outcome forecast pathogen prevent response therapeutic target

项目摘要

Project Summary Necrotizing enterocolitis (NEC) is the most common surgical emergency in the neonatal period. Despite advances in medical care, mortality and morbidity caused by NEC has not changed in the past three decades. This is largely due to a poor understanding of the complex pathogenesis of this multifactorial diseases and by the lack of specific therapies. We have preliminary data showing the histones-DNA complexes are elevated in premature infants with NEC. Studies from our lab and others identified extracellular histones as major mediators in many pathological conditions including sepsis, thrombosis, and trauma. In humans and animal models of sepsis, high levels of histones-DNA correlate with organ failure and mortality. Moreover, histone inhibition with specific antibodies reduces mortality in LPS- and/or E.coli challenged animals, prevents ischemia-reperfusion and endotoxin induced acute kidney injury, and thrombocytopenia. All these data suggest that histones are relevant biomarkers and therapeutic targets in pathologic conditions that involve tissue necrosis and inflammation. Histones are released into the extracellular environment either passively by apoptotic or necrotic cells, or actively as neutrophil extracellular traps (NETs). NETs formation is a new paradigm of cell death where neutrophils release their nuclear contents in response to infection or other stimuli. Although NETs aid in trapping bacteria and other pathogens, their prolonged presence may lead to adjacent tissue damage. We have data showing the presence of NETs in intestinal tissue of premature infants with NEC. Whether NETs and their components, specifically histones, contribute to intestinal injury and disease progression in NEC is still unknown. Thus we aim in this proposal to investigate the role of histones and NETs in NEC pathology by (i) determining whether histones-DNA levels are biomarkers of poor prognosis in premature infants with NEC; (ii) characterizing histones' release and NETs formation in mouse models of NEC, and (iii) investigating the effects of histones inhibitors and NET formation using pharmacological and genetic approaches in experimental NEC. Over all this project will potentially advance our understanding of NEC, describe new biomarkers, and lead to novel therapeutic strategies for this highly lethal disease.

项目概要坏死性小肠结肠炎（NEC）是新生儿期最常见的外科急症。尽管医疗保健的进步、NEC 造成的死亡率和发病率在过去三十年中没有改变。这主要是由于对这种多因素疾病的复杂发病机制了解不足以及缺乏具体的治疗方法。我们有初步数据显示早产儿的组蛋白-DNA 复合物升高 NEC。我们实验室和其他实验室的研究发现细胞外组蛋白是许多病理学中的主要介质病症包括脓毒症、血栓形成和创伤。在败血症的人类和动物模型中，高水平的组蛋白-DNA 与器官衰竭和死亡率相关。此外，用特异性抗体抑制组蛋白降低 LPS 和/或大肠杆菌攻击动物的死亡率，预防缺血再灌注和内毒素诱发急性肾损伤和血小板减少症。所有这些数据表明组蛋白是相关的生物标志物以及涉及组织坏死和炎症的病理状况的治疗目标。组蛋白通过凋亡或坏死细胞被动释放到细胞外环境中，或主动作为中性粒细胞胞外陷阱（NET）。 NETs 的形成是细胞死亡的一种新范式，其中中性粒细胞响应感染或其他刺激而释放其核内容物。尽管 NET 有助于捕获细菌和其他病原体，它们的长期存在可能会导致邻近组织损伤。我们有数据显示患有 NEC 的早产儿肠道组织中存在 NET。无论是 NET 及其导致 NEC 肠道损伤和疾病进展的成分，特别是组蛋白，目前仍不清楚。因此，我们在本提案中的目的是通过 (i) 确定组蛋白和 NET 在 NEC 病理学中的作用组蛋白-DNA 水平是否是早产儿 NEC 预后不良的生物标志物； (二) 表征 NEC 小鼠模型中组蛋白的释放和 NET 的形成，以及 (iii) 研究组蛋白的影响在实验性 NEC 中使用药理学和遗传学方法抑制抑制剂和 NET 形成。总的来说，这个项目将有可能增进我们对 NEC 的理解，描述新的生物标志物，以及为这种高度致命的疾病带来新的治疗策略。