Novel Strategies for Prevention of Necrotizing Enterocolitis

预防坏死性小肠结肠炎的新策略

• 批准号: 10341205
• 负责人: Hala Chaaban
• 金额: $ 27.51万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10341205
• 关键词: Animal Model; Bacteria; Bacterial Translocation; Biological; Brain Hypoxia-Ischemia; Caring; Cesarean section; Cessation of life; Clinical; Colitis; Complex; Critical Care; Data; Defensins; Development; Disease; Emergency Situation; Enterocytes; Epithelial; Etiology; Exhibits; Exposure to; Extracellular Matrix; Gastrointestinal Diseases; Glucosamine; Glucuronic Acids; Glycosaminoglycans; Goals; Goblet Cells; Growth; Growth Factor; Histology; Human; Human Milk; Hyaluronan; Hypoxia; Immunity; Immunology; Impairment; In Vitro; Infant; Infant Care; Inflammation; Inflammatory Response; Intervention; Intestinal permeability; Intestines; Investigation; Lactoferrin; Large Intestine; Lead; Medical; Modeling; Modification; Molecular Weight; Morbidity - disease rate; Mucous body substance; Multiple Organ Failure; Mus; Necrosis; Necrotizing Enterocolitis; Oklahoma; Oligosaccharides; Oral; Paneth Cells; Papio; Pathogenesis; Patient-Focused Outcomes; Play; Premature Infant; Prevalence; Prevention strategy; Preventive therapy; Proteins; RNA analysis; Reporting; Reproducibility; Research; Risk; Role; Sepsis; Severities; Small Intestines; Stains; Systemic Inflammatory Response Syndrome; TLR4 gene; Therapeutic; Tight Junctions; Tissues; Translations; antimicrobial; antimicrobial peptide; base; beta-Defensins; biomarker discovery; claudin 3; clinical care; clinical practice; clinically relevant; commensal bacteria; feeding; gastrointestinal; gut inflammation; gut microbiome; improved; in vivo; intestinal barrier; intestinal epithelium; intestinal homeostasis; intestinal injury; intestinal maturation; microbial; microbiome; mortality; mouse model; neonatal period; nonhuman primate; novel; novel strategies; occludin; prebiotics; pregnant; premature; preterm newborn; prevent; protective effect; protective factors; pup; response; systemic inflammatory response

Project Summary Necrotizing enterocolitis (NEC) is one of the most common gastrointestinal emergency in the neonatal period. It is characterized by severe intestinal inflammation that can rapidly result in intestinal necrosis, sepsis, and potentially death. Despite advances in medical care, mortality and morbidity caused by NEC has not changed. This is largely due to the poor understanding of the complex pathogenesis, the limitations of the current animal models, and the lack of specific therapeutic or preventative therapies. Although the etiology is unclear, evidence suggests that prematurity, formula feeding, altered intestinal microbiome, and hypoxia-ischemia play major roles in NEC. Preterm infants have impaired intestinal permeability, and exhibit prominent intestinal epithelial TLR4 expression; all of which render the bowel at risk of bacterial translocation, an exaggerated inflammatory response, and NEC development. Therefore, identifying strategies or interventions that promote maturation of intestinal defenses, epithelial integrity, and modulate inflammation is critical in preventing this deadly disease. We have promising preliminary data demonstrating that oral hyaluronan at a molecular weight of ~ 35 kDa (HA 35kDa) reduces mortality, severity of intestinal injury, and systemic inflammation in a murine model of NEC. HA is a glycosaminoglycan found in almost all tissues including extracellular matrix. Studies showed that HA isolated from breast milk or commercially available HA 35kDA, protects against bacteria-induced colitis by increasing the expression of antimicrobial β-defensins, and tight junction protein ZO-1 in colonic epithelium in vivo and in vitro. Based on our preliminary data and the previously reported biological effects of HA in the large intestine, we propose to directly investigate the effect of HA 35kDa on the (1) immature intestinal defenses, specifically antimicrobial peptides produced by enterocytes and Paneth cells, (2) intestinal barrier including mucous lining and TJ formation, and (3) on the development of the intestinal microbiome in healthy pups and pups with NEC (Aim 1).To facilitate translation of our results to human studies, we propose to evaluate the effect of HA 35kDa on a novel premature non-human primate model (NHP) of NEC (Aim 2). The ultimate goal of this project to initiate a new research direction in a disease that has shown little clinical progress over the past 50 years. Results from our study would enhance our understanding of NEC and lead to identification of new preventative strategies that will improve patient outcomes.

项目摘要 坏死性小肠结肠炎是新生儿最常见的消化道急症之一 期其特征是严重的肠道炎症，可迅速导致肠坏死，败血症， 甚至可能死亡尽管医疗保健取得了进步，但NEC引起的死亡率和发病率并没有 变了这在很大程度上是由于对复杂的发病机制认识不足，目前研究的局限性， 动物模型，以及缺乏特定的治疗或预防疗法。 虽然病因尚不清楚，但有证据表明，早产、配方奶粉喂养、肠道改变 微生物组和缺氧缺血在NEC中起主要作用。早产儿肠道功能受损 通透性，并表现出突出的肠上皮TLR 4表达;所有这些都使肠处于 细菌移位、过度炎症反应和NEC发展。因此，识别 促进肠防御成熟、上皮完整性和调节 炎症是预防这种致命疾病的关键。 我们有很有希望的初步数据表明，口服透明质酸在分子量约35 kDa（HA 35 kDa）可降低小鼠模型的死亡率、肠道损伤的严重程度和全身炎症 NEC。HA是一种糖胺聚糖，存在于几乎所有组织中，包括细胞外基质。研究表明 从母乳中分离的HA或市售HA 35 kDA，通过以下方式预防细菌诱导的结肠炎： 增加结肠上皮中抗微生物β-防御素和紧密连接蛋白ZO-1的表达， 体内和体外。根据我们的初步数据和以前报道的HA在大范围内的生物学效应， 肠，我们建议直接研究HA 35 kDa对（1）未成熟肠防御的影响， 特别是由肠细胞和潘氏细胞产生的抗微生物肽，（2）肠屏障，包括 粘液衬里和TJ形成，和（3）对健康幼仔肠道微生物组的发育， 为了便于将我们的结果转化为人类研究，我们建议评估NEC的效果， HA 35 kDa在NEC的新型早产非人灵长类动物模型（NHP）上的表达（目的2）。 该项目的最终目标是在一种几乎没有表现出的疾病中开创一个新的研究方向。 近50年来的临床进展。我们的研究结果将增进我们对NEC的了解， 导致识别新的预防策略，将改善患者的结果。