The zebrafish, Danio rerio, is a powerful model system to elucidate novel factors and mechanisms underlying intestinal pathology in humans. The developing embryos have a functioning motile gastrointestinal system including a liver, pancreas, gallbladder and intestine by four days after fertilization. The optical clarity of the zebrafish embryos allows direct observation of the development and function of these organs. These specific characteristics of the zebrafish gastrointestinal system, as well as the wide-spread utilization of the zebrafish to model many other human disease processes, make the zebrafish a powerful system to utilize in both forward mutagenesis screens and reverse over and misexpression studies to identify the genes that control intestinal development. Utilizing an insertional forward genetic screening approach, we have isolated a number of zebrafish mutants with defects in gastrointestinal development. We are focusing our studies on three of those mutant lines demonstrating minimal alterations outside of the gastrointestinal tract, whose underlying genetic defects have been characterized and have not been previously implicated in gastrointestinal development.
In Specific aim 1, we will determine the functional significance of each gene in gastrointestinal development.
In Specific aim 2 we will determine the developmental block in mutants by studying the developmental expression of various gastrointestinal markers in mutant embryos.
In specific aim 3, we will determine the epistatic interactions between the mutants in promoting gastrointetsinal development. Our hypothesis is that these three mutants characterize novel pathways involved in the patterning and growth of the gastrointestinal system. Small perturbations in the growth and function of the gastrointestinal tract have severe consequences and underlie human pathologies as varied as structural birth defects, inflammatory bowel disease and gastrointestinal malignancy. These studies will provide needed insights into novel pathways of gastrointestinal development and function, which can form the basis for new therapeutic strategies by which we can prevent or treat gastrointestinal pathology. ? ?

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Exploratory/Developmental Grants (R21)
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Gastrointestinal Cell and Molecular Biology Study Section (GCMB)
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Karp, Robert W
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University of Pittsburgh
Schools of Medicine
United States
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Thakur, Prakash C; Davison, Jon M; Stuckenholz, Carsten et al. (2014) Dysregulated phosphatidylinositol signaling promotes endoplasmic-reticulum-stress-mediated intestinal mucosal injury and inflammation in zebrafish. Dis Model Mech 7:93-106
Stuckenholz, Carsten; Lu, Lili; Thakur, Prakash C et al. (2013) Sfrp5 modulates both Wnt and BMP signaling and regulates gastrointestinal organogenesis [corrected] in the zebrafish, Danio rerio. PLoS One 8:e62470
Thakur, Prakash C; Stuckenholz, Carsten; Rivera, Marcus R et al. (2011) Lack of de novo phosphatidylinositol synthesis leads to endoplasmic reticulum stress and hepatic steatosis in cdipt-deficient zebrafish. Hepatology 54:452-62
Stuckenholz, Carsten; Lu, Lili; Thakur, Prakash et al. (2009) FACS-assisted microarray profiling implicates novel genes and pathways in zebrafish gastrointestinal tract development. Gastroenterology 137:1321-32