Brief background of the proposal and its relevance to the CDI’s objectives
Necrotizing enterocolitis (NEC) is a devastating gastrointestinal disorder that primarily affects premature infants. The predominant feature of this disease is the loss of the intestinal epithelial cell barrier and necrosis. Currently, there are no therapeutics that block the induction or progression of NEC. Moreover, current animal models are too costly and cumbersome to screen for compounds that block NEC. This proposed project will use a recently described Caenorhabditis elegans (C. elegans) model of intestinal cell necrosis to develop and perform pilot drug screens in vivo for compounds that could prevent necrosis and be tested in mammalian models.
Proposed Specific Aims
· Develop an automated C. elegans assay for high-content screening of intestinal cell necrosis.
· Perform pilot drug screens for compounds that block necrotic cell death in C. elegans.
· Validate promising hit compounds in mouse ex vivo models of intestinal injury.
Potential impact on child health
This multidisciplinary approach combining cell biology, animal models, and drug discovery has the potential to reveal therapeutic compounds for NEC, as well as other pediatric diseases where necrotic cell death plays a major role.