Novel Strategies for Prevention of Necrotizing Enterocolitis

预防坏死性小肠结肠炎的新策略

• 批准号: 10554357
• 负责人: Hala Chaaban
• 金额: $ 26.34万
• 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 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10554357
• 关键词: Acceleration; Animal Model; Bacteria; Bacterial Translocation; Biological; Brain Hypoxia-Ischemia; Caring; Cesarean section; Cessation of life; Clinical; Colitis; Colon; Complex; Critical Care; Data; Defensins; Development; Disease; Emergency Situation; Enterocytes; Epithelium; 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; Medical; Modeling; Modification; Molecular Weight; Morbidity - disease rate; Mucous body substance; Multiple Organ Failure; Mus; Necrosis; Necrotizing Enterocolitis; Oklahoma; Oligosaccharides; Oral; Oral Administration; 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; 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（NEC）是新生儿中最常见的胃肠道紧急事件之一 时期。它的特征是严重的肠道炎症，可能会迅速导致肠道坏死，败血症， 并可能死亡。尽管医疗服务的进步，NEC引起的死亡率和发病率尚未 改变了。这在很大程度上是由于对复杂发病机理的不良理解，电流的局限性 动物模型，缺乏特定的治疗或预防疗法。 尽管病因不清 微生物组和缺氧 - 缺血症在NEC中起主要作用。早产婴儿肠道受损 渗透性，表现出突出的肠上皮TLR4表达；所有这些都使肠子有风险 细菌易位，夸张的炎症反应和NEC发育。因此，识别 促进肠道防御，上皮完整性和调节的策略或干预措施 炎症对于预防这种致命疾病至关重要。 我们已承诺初步数据表明，分子量的口服透明质酸〜35 KDA（HA 35KDA）在鼠模型中降低了死亡率，肠道损伤的严重程度和全身感染 NEC。 HA是在包括细胞外基质在内的几乎所有组织中发现的糖胺聚糖。研究表明 HA从母乳或市售HA 35KDA中分离出来，可预防细菌诱导的结肠炎 增加结肠上皮中抗菌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先前报道的HA在大型中的生物学作用 肠，我们建议直接研究HA 35KDA对（1）不成熟肠道防御的影响， 特别是由肠上皮细胞和泛细胞产生的抗菌胡椒粉，（2）包括 粘膜衬里和TJ形成，以及（3）关于健康幼崽中肠道微生物组的发展 具有NEC的幼崽（AIM 1）。为了促进我们的结果转化为人类研究，我们建议评估效果 NEC的新型非人类主要模型（AIM 2）的新型非人类素数模型（NHP）。 该项目的最终目标是在疾病中引发新的研究方向 在过去的50年中，临床进展。我们研究的结果将增强我们对NEC和NEC的理解 导致确定将改善患者预后的新预防策略。