Hirschsprung disease (HSCR) is a leading cause of intestinal dysmotility resulting from a reduced enteric nervous system (ENS) and leading to lack of distal intestine innervations. HSCR can be caused by mutations in several different loci and shows considerable phenotypic variation: individuals carrying the same allele can differ in the extent of intestinal denervation and severity of enterocolitis, intestinal inflammation of unknown etiology that is a serious HSCR complication. The sources of these phenotypic variations in HSCR are not well understood. If we could identify factors that make some individuals healthier than others, we would gain insight into potential therapies for those with more serious disease. We have a panel of zebrafish ENS mutants that serve as models for understanding variation in HSCR. Zebrafish is an excellent model in which to study HSCR phenotypic variation because we can manipulate all of the relevant parameters. Our zebrafish mutants have different extents of distal intestine denervation, often with considerable phenotypic variation among mutants that share the same genotype. These mutants also exhibit variation in intestinal motility, variation in their intestinal bacterial communities, and variation in intestinal inflammation. We propose that alterations in the ENS phenotype in ENS mutants, including changes in specific neuronal subtypes, result in dysmotility that causes changes in the milieu of the intestinal lumen. This, in turn, can lead to formation of altered bacterial communities that can cause inflammation by recruiting neutrophils, cells of the innate immune system that respond to bacteria and are a hallmark of intestinal inflammation. We also propose that changes in the intestinal bacterial community composition and in inflammation can feed back to the ENS to amplify variation in intestinal motility. We will test these hypotheses by manipulating the ENS phenotype, intestinal bacterial composition, and neutrophil influx and comparing all of these processes in individual animals of known genotypes. We will follow bacterial colonization, neutrophil recruitment, and intestinal motility in living animals in real time. Our proposed studies will provide new information about how the ENS regulates the composition of the intestinal bacterial community and inflammation, and how these processes feed back onto the ENS to amplify intestinal pathology. This information will provide new insights into the mechanisms of phenotypic variation in HSCR, expand our understanding of phenotypic variation in human disease, and may reveal new targets for therapies.

Public Health Relevance

Hirschsprung disease is a prevalent cause of intestinal dysmotility, affecting 1:5000 live births, and is often accompanied by debilitating intestinal enterocolitis of unknown origin. The proposed studies use zebrafish models to uncover the origins of variation in Hirschsprung-associated intestinal pathology and enterocolitis, paving the way toward better clinical diagnoses and treatments.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Program Projects (P01)
Project #
5P01HD022486-27
Application #
8737027
Study Section
Special Emphasis Panel (ZHD1-DSR-Y)
Project Start
Project End
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
27
Fiscal Year
2014
Total Cost
$349,755
Indirect Cost
$108,545
Name
University of Oregon
Department
Type
DUNS #
948117312
City
Eugene
State
OR
Country
United States
Zip Code
97403
Edmunds, Richard C; Su, Baofeng; Balhoff, James P et al. (2016) Phenoscape: Identifying Candidate Genes for Evolutionary Phenotypes. Mol Biol Evol 33:13-24
Burns, Adam R; Stephens, W Zac; Stagaman, Keaton et al. (2016) Contribution of neutral processes to the assembly of gut microbial communities in the zebrafish over host development. ISME J 10:655-64
Mason, Timothy; Snell, Kathy; Mittge, Erika et al. (2016) Strategies to Mitigate a Mycobacterium marinum Outbreak in a Zebrafish Research Facility. Zebrafish :
Wiles, Travis J; Jemielita, Matthew; Baker, Ryan P et al. (2016) Host Gut Motility Promotes Competitive Exclusion within a Model Intestinal Microbiota. PLoS Biol 14:e1002517
Hill, Jennifer Hampton; Franzosa, Eric A; Huttenhower, Curtis et al. (2016) A conserved bacterial protein induces pancreatic beta cell expansion during zebrafish development. Elife 5:
Zac Stephens, W; Burns, Adam R; Stagaman, Keaton et al. (2016) The composition of the zebrafish intestinal microbial community varies across development. ISME J 10:644-54
Talbot, Jared Coffin; Nichols, James T; Yan, Yi-Lin et al. (2016) Pharyngeal morphogenesis requires fras1-itga8-dependent epithelial-mesenchymal interaction. Dev Biol 416:136-48
Taylor, Charlotte R; Montagne, William A; Eisen, Judith S et al. (2016) Molecular fingerprinting delineates progenitor populations in the developing zebrafish enteric nervous system. Dev Dyn 245:1081-1096
Desvignes, Thomas; Detrich 3rd, H William; Postlethwait, John H (2016) Genomic conservation of erythropoietic microRNAs (erythromiRs) in white-blooded Antarctic icefish. Mar Genomics 30:27-34
Postlethwait, John H; Yan, Yi-Lin; Desvignes, Thomas et al. (2016) Embryogenesis and early skeletogenesis in the antarctic bullhead notothen, Notothenia coriiceps. Dev Dyn 245:1066-1080

Showing the most recent 10 out of 295 publications