Premature infants face a host of unique issues due to their developmental immaturity. One of the most devastating is necrotizing enterocolitis (NEC), which yearly kills 12 babies per 100,000 live births in the USand frequently leaves survivors with severe feeding issues, liver failure, and neurodevelopmental disability. Understanding mechanisms of intestinal injury and repair in developing intestine is key to developing new prevention and therapeutic strategies for NEC. This proposal will investigate the mechanisms of gastrointestinal epithelial cell injury and repair duringdevelopment by testing the hypothesis that the intestine of premature infants and newborn mice is more susceptible to TNF-induced injury because of an ontogenically normal decrease in expression and activation of EGFR. This hypothesis will be examined through the following specific Aims: 1) Define the effects of TNF on intestinal injury and apoptosis at different developmental stages. This will be accomplished using histopathologic injury scores of early intestinal damage as well as immunofluorescence and immunohistochemicalassays for apoptosis;2) Determine the effects of TNF on EGFR inhibition in neonates compared to adults. We will study the effects of TNFon multipleEGFR phosphorylation sites and down-stream targets, and the role of EGFR internalization in TNF-stimulatedEGFR inhibition.
This aim willutilize immunofluorescence and western blot analysis to study the down-stream targets of EGFR activation;and 3) Determine the role of EGFR activation in protecting against TNFinduced injury using pharmacologic and genetic models of EGFR activation.
This aim will build on techniques developed in Aim 1 and 2 and apply them to mice with constitutively active EGFR, pharmacologicallyactive EGFR, and deficiency of EGFR. Overall,these studies will reveal the roles of TNFand EGFR in intestinal injury processes in developing intestinal tissue, and will identify potential novel avenues oftherapy and chemoprevention. In addition to the above studies, this proposal will greatly enhance career development through didactic training in cell biology, developmental biology, and statistics;by providing mentoring from a strong laboratory;and by utilizing the strong resources uniquely available at Vanderbilt to foster independent investigation in gastrointestinal disease.

Public Health Relevance

Necrotizing enterocolitis is a form of acute intestinal injury that is a leading cause of death and poor outcomes in premature infants. The studies in this proposal are intended to understand the mechanisms of injury and repair in the developing intestine of prematurely born infants, and the development of novel therapeutic approaches to prevent or ameliorate this devestating illness.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08DK083677-05
Application #
8317682
Study Section
Special Emphasis Panel (ZDK1-GRB-7 (J2))
Program Officer
Podskalny, Judith M,
Project Start
2009-07-01
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
5
Fiscal Year
2012
Total Cost
$144,980
Indirect Cost
$10,739
Name
University of Iowa
Department
Pediatrics
Type
Schools of Medicine
DUNS #
062761671
City
Iowa City
State
IA
Country
United States
Zip Code
52242
McElroy, Steven J; Castle, Shannon L; Bernard, Jessica K et al. (2014) The ErbB4 ligand neuregulin-4 protects against experimental necrotizing enterocolitis. Am J Pathol 184:2768-78
McElroy, S J (2014) Unraveling the enigma that is neonatal necrotizing enterocolitis. J Perinatol 34:729-30
Brown, Kathryn S; Gong, Huiyu; Frey, Mark R et al. (2014) Tumor necrosis factor induces developmental stage-dependent structural changes in the immature small intestine. Mediators Inflamm 2014:852378
McElroy, Steven J; Underwood, Mark A; Sherman, Michael P (2013) Paneth cells and necrotizing enterocolitis: a novel hypothesis for disease pathogenesis. Neonatology 103:10-20
Zhang, Chunxian; Sherman, Michael P; Prince, Lawrence S et al. (2012) Paneth cell ablation in the presence of Klebsiella pneumoniae induces necrotizing enterocolitis (NEC)-like injury in the small intestine of immature mice. Dis Model Mech 5:522-32
McElroy, Steven J; Prince, Lawrence S; Weitkamp, Jorn-Hendrik et al. (2011) Tumor necrosis factor receptor 1-dependent depletion of mucus in immature small intestine: a potential role in neonatal necrotizing enterocolitis. Am J Physiol Gastrointest Liver Physiol 301:G656-66