Prevention of Necrotizing Enterocolitis

预防坏死性小肠结肠炎

• 批准号: 10655139
• 负责人: Hala Chaaban
• 金额: $ 40.94万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10655139
• 关键词: 3-Phosphoinositide Dependent Protein Kinase-1; Acceleration; Adult; Affect; Attenuated; Bacterial Infections; Bacterial Translocation; Cell Count; Cessation of life; Colitis; Colostrum; Complex; Data; Development; Disease; Dithizone; Emergency Situation; Enteral; Enterocytes; Epithelial Cells; Epithelium; FRAP1 gene; Family; Glycosaminoglycans; Goals; Goblet Cells; Homeostasis; Human; Human Milk; Hyaluronan; Hypoxia; Immunohistochemistry; Impairment; Infant; Inflammation; Injury; Intervention; Intestinal permeability; Intestines; Invaded; Klebsiella Infections; Knockout Mice; Lactation; Large Intestine; Literature; Measures; Mediating; Modeling; Mucous Membrane; Multiple Organ Failure; Mus; Natural regeneration; Necrosis; Necrotizing Enterocolitis; Newborn Infant; Oral; Oral Administration; PIK3CG gene; Paneth Cells; Pathogenesis; Pathology; Pathway interactions; Phosphotransferases; Play; Premature Infant; Prevention; Prevention strategy; Preventive therapy; Proliferating; Protein-Serine-Threonine Kinases; Proteins; Proto-Oncogene Proteins c-akt; Radiation Injuries; Regenerative capacity; Risk; Role; Scientist; Severities; Signal Pathway; Signal Transduction; Sirolimus; Small Intestines; TSC1 gene; Testing; Therapeutic; Tight Junctions; Tissues; Western Blotting; conditional knockout; dietary supplements; dysbiosis; epithelial injury; epithelial repair; epithelium regeneration; feeding; gastrointestinal; genetic approach; gut inflammation; injured; insight; intestinal barrier; intestinal epithelium; intestinal homeostasis; intestinal injury; intestinal maturation; kinase inhibitor; member; mortality; mouse model; novel; novel strategies; pharmacologic; postnatal; premature; prevent; protective effect; pup; stem cells; systemic inflammatory response; transcriptome sequencing; wound healing

Project Summary/Abstract Necrotizing enterocolitis (NEC) is the most devastating gastrointestinal pathology in the newborn period. Although the pathogenesis is unclear, evidence suggests prematurity and formula feeding play major roles in NEC. Our long-term goal is to identify strategies that promote postnatal maturation and barrier function in infants at risk of NEC. Our compelling data show that hyaluronan (HA) in human milk (HM) is a promising bioactive factor that accelerate small intestinal maturation and protect against the development of NEC. HA is a unique nonsulfated glycosaminoglycan present in high concentrations in colostrum and HM in the first weeks of lactation. We previously showed that oral administration of 35kDa HA ( HA35), a mimic of HM HA, increases intestinal epithelial proliferation, differentiation into Paneth and goblet cells, and expression of tight junction proteins. We also showed that oral HA35 reduces the severity of the intestinal injury, bacterial translocation, and decreases mortality in a NEC-like intestinal injury model. Using RNA-Seq, immunohistochemistry, and western blot analyses, we identified the mechanistic target of rapamycin (mTOR) complex 1 (mTORC1)-mediated pathway was upregulated in ileal tissues by HA35 treatment. mTOR is a serine/threonine-protein kinase and a member of the PI3K-related kinase family, which complexes mTORC1 and mTORC2. Studies suggest mTORC1 regulates Paneth and goblet cells under normal conditions, and promotes intestinal stem cell activity and epithelial repair post-radiation injury and adult colitis model. Despite emerging evidence supporting its critical role in epithelial homeostasis and regeneration, the role of mTORC1 in NEC is largely unknown. We hypothesize that the effects of HA35 are mediated, at least in part, through activation of the mTORC1 signaling pathway. Since activation of mTORC1 promotes proliferation, differentiation, and regeneration of the gut, we also hypothesize that modulating the mTORC1 pathway is a potential therapeutic approach in preventing/treating NEC. At the end of this project, we will : (i) determine the role of HA35 and mTORC1 signaling in homeostasis and in NEC-like injury models (ii) understand the involvement of the mTOR pathway in the pathogenesis of NEC; and (iii) establish the basis of HA35 as a novel dietary supplement that promotes epithelial protection in infants at risk of NEC. To achieve these goals, we assembled a well-integrated team of scientists and clinicians with complementary expertise in mTORC1 signaling pathway, murine modeling of NEC, and human premature enteroid models of intestinal development and injury. The results of our proposal have the potential to greatly enhance our understanding of NEC pathogenesis, and potentially provide novel insight into effective preventative therapies.

项目摘要/摘要 坏死性小肠结肠炎（NEC）是新生儿时期最具破坏性的胃肠道病理。 尽管发病机理尚不清楚，但证据表明早产性和配方奶粉在 NEC。我们的长期目标是确定促进婴儿后成熟和障碍功能的策略 有NEC的风险。我们引人注目的数据表明，人乳（HM）中的透明质酸（HA）是一种有希望的生物活性 加速肠道成熟并防止NEC发展的因素。哈是一个独特的 在哺乳期的头几周内，非硫化的糖胺聚糖在初乳和HM中以高浓度存在。 我们先前表明，口服35KDA HA（HA35）是HM HA的模仿，增加了肠道 上皮增殖，分化为Paneth和Goblet细胞，以及紧密连接蛋白的表达。我们 还表明口服HA35降低了肠损伤，细菌易位的严重程度，并减少 NEC样肠损伤模型中的死亡率。使用RNA-seq，免疫组织化学和Western印迹 分析，我们确定了雷帕霉素（MTOR）复合物1（MTORC1）介导的途径的机械靶标 通过HA35处理在回肠组织中上调。 MTOR是丝氨酸/苏氨酸蛋白激酶，成员 与PI3K相关的激酶家族的复合物。研究表明MTORC1 调节正常条件下的潘妮和杯状细胞，并促进肠道干细胞活性和 上皮修复后辐射损伤和成人结肠炎模型。尽管有新兴的证据支持其关键 在上皮稳态和再生中的作用，MTORC1在NEC中的作用在很大程度上是未知的。我们假设 HA35的作用至少部分是通过激活MTORC1信号通路介导的。 由于MTORC1的激活促进了肠道的增殖，分化和再生，因此我们也 假设调节MTORC1途径是预防/治疗的潜在治疗方法 NEC。在该项目结束时，我们将：（i）确定HA35和MTORC1信号在体内平衡中的作用 在NEC样损伤模型（II）中，了解MTOR途径在NEC发病机理中的参与； （iii）建立HA35的基础作为一种新型的饮食补充剂，可促进婴儿上皮保护 有NEC的风险。为了实现这些目标，我们与 MTORC1信号通路，NEC的鼠建模和人类早产的互补专业知识 肠发育和损伤的肠道素模型。我们提案的结果有可能极大地 增强我们对NEC发病机理的理解，并有可能对有效预防的新见解 疗法。