Novel Strategies for Prevention of Necrotizing Enterocolitis

项目摘要 坏死性小肠结肠炎(NEC)是新生儿最常见的胃肠道急症之一。 句号。它的特点是严重的肠道炎症，可迅速导致肠坏死、脓毒症、 甚至有可能死亡。尽管医疗保健取得了进步，但由NEC引起的死亡率和发病率并没有 变化。这在很大程度上是由于对复杂的发病机制认识不足，目前的局限性 动物模型，以及缺乏特定的治疗性或预防性治疗。 虽然病因尚不清楚，但有证据表明，早产、配方奶喂养、肠道改变 微生物组和缺氧缺血在NEC中起主要作用。早产儿肠道受损 通透性，并表现出明显的肠道上皮细胞TLR4表达；所有这些都使肠道面临 细菌移位、夸大的炎症反应和NEC的发展。因此，识别 促进肠道防御成熟、上皮完整性和调节的策略或干预措施 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，口服透明质酸的相对分子质量为35 KDA(HA 35 KDa)可降低小鼠死亡率、肠道损伤严重程度和全身炎症反应 NEC。HA是一种糖胺多聚糖，几乎存在于所有组织中，包括细胞外基质。研究表明， 从母乳或市售HA 35kDA中分离出来的HA可通过以下方式预防细菌引起的结肠炎 β-防御素和紧密连接蛋白ZO-1在大鼠结肠上皮细胞中的表达 体内和体外。根据我们的初步数据和之前报道的HA的生物学效应 肠，我们建议直接研究HA 35 kDa在(1)未成熟肠道防御中的作用。 特别是肠细胞和潘氏细胞产生的抗菌肽，(2)肠屏障，包括 粘液衬里和TJ的形成，以及(3)对健康幼崽和 PUPS与NEC(目标1)。为了便于将我们的结果转化为人体研究，我们建议评估其效果 在NEC的一个新的早产儿非人类灵长类动物模型(NHP)上表达HA 35 kDa(目标2)。 这个项目的最终目标是开启一种新的研究方向，研究一种几乎没有表现出来的疾病 过去50年的临床进展。我们的研究结果将加深我们对NEC和 导致确定新的预防策略，以改善患者的预后。

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.