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.