Gene-environment interactions in necrotizing enterocolitis: impact of SIGIRR mutation and gut microbiota on intestinal TLR hyperactivity

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PROJECT SUMMARY/ABSTRACT This NIH K08 proposal describes a five-year training and research plan for the candidate, a physician-scientist with a long-term goal of becoming an independent investigator in the field of neonatal medicine. Toward this end, the proposed research is directed at defining the pathogenesis of necrotizing enterocolitis (NEC) – a devastating inflammatory bowel disease of preterm infants that is characterized mainly by the excessive activation of the Toll-Like Receptor (TLR) family of innate immune receptors. Inherent genetic susceptibility and the intestinal microbiota environment are two factors strongly implicated in NEC pathogenesis. These factors have primarily been evaluated in isolation from each other – an important limitation that does not replicate the complex nature of NEC. Recently, our laboratory generated novel transgenic mice that recapitulate a mutation discovered in infants with NEC. This mutation is a stop mutation of Single-Immunoglobulin Interleukin-1 Related Receptor (SIGIRR), a gene that normally functions to inhibit gut TLR signaling. The generated SIGIRR transgenic mice (SIGIRRTG) exhibit a phenotype of increased gut TLR activity at baseline conditions. In this study, the candidate proposes to use this novel mouse line as a genetic model of NEC to determine the interaction between genetics and the gut microbiome as it relates to gut TLR activity. Aim #1 will determine the impact of SIGIRR mutation on gut microbiota signatures. Aim #2 will determine whether increased intestinal TLR activity in SIGIRRTG mice is driven by gut microbiota. Aim #3 will determine the effect of gut microbiome alteration in reversing genetic predisposition of SIGIRRTG mice towards intestinal inflammation. Completion of these aims will provide novel insights into how genes and the gut microbiome interact to influence TLR homeostasis in the developing gut. New knowledge gained will represent a significant advancement in understanding the complex pathogenesis of NEC that can be used to inform the development of personalized, microbiome-based therapies for NEC. The candidate is firmly committed to a career in basic and translational NEC research and is strongly supported in his career and research goals by his mentors and his department at Children’s Mercy Kansas City. He currently holds a position as an Assistant Professor of Pediatrics with 75% protected time for research, independent laboratory and office space, and start-up funding. The current proposal includes a comprehensive mentorship and didactic plan to advance the candidate’s skills and knowledge in TLR biology, microbial pathogenesis, cell and molecular biology, microbiome sequencing, bioinformatics, and research ethics. Completion of this comprehensive training plan will provide the candidate with the skills and experience necessary to develop an independent research program and obtain R01 funding.