Prevention of Necrotizing Enterocolitis

项目总结/文摘

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.