This NIDDK Mentored Research Scientist Development Award application describes a 5-year training plan designed to allow me to gain additional skill and knowledge so that I can transition into an independent research scientist. In carrying out the proposed research, and by following my career development plan I will add to my scientific repertoire and acquire expertise in intestinal developmental biology. Using this newly acquired expertise in intestine development, I will establish a scientific niche that will set me apart from my mentors and pave the way to a robust, extramurally funded research program. The research proposed in this application will focus on understanding how the stem/progenitor cells in the embryonic intestine are specified and regulated using both traditional mouse genetics, and a novel in vitro system we have developed that allows us to generate human intestinal tissue in culture from human embryonic and induced pluripotent stem cells. Generation of human intestinal tissue in culture will allow for unprecedented studies of human intestinal development, homeostasis and disease.
The specific aims are designed to test a model where Sox9 regulates early intestinal progenitor cells as they are restricted to the proliferative intervillus region of the developing intestine.
Specific Aim 1 will investigate the embryonic development of human and mouse intestinal stem cells using lineage labeling and cell tracing experiments.
Specific Aim 2 will determine the role of Sox9 in regulating embryonic development of the intervillus region in human and mouse intestine.
Specific Aim 3 will investigate a suppressive role for Wnt signaling in establishment of the intervillus progenitor zone during development. Collectively, the research proposed here is in line with the Trans-NIH Report """"""""Opportunities and Challenges in Digestive Diseases Research: Recommendations of the National Commission on Digestive Diseases"""""""" (2009) which states: """"""""Uncovering the mechanisms that control development and differentiation of the digestive tract before birth and in neonatal life could generate new insights for regenerative therapies to treat digestive cancers and other diseases, as well as provide new insights into disease pathogenesis."""""""" The goal of this Mentored Research Scientist Development Award is to develop the expertise that will allow me to run an independent, funded research program that will contribute to improving human health and disease.
Diseases that affect the prenatal and perinatal digestive tract include Necrotizing Enterocolitis (NEC) and Short Bowel Syndrome (SBS), and lead to increased rates of mortality and morbididity in preterm infants. Regenerative therapies designed at improving the outcomes of these and other diseases require insights into how the fetal intestine develops. This research proposal uses a novel system to study human fetal intestinal development in culture, and is designed to investigate how the proliferative cells of the developing intestine are established and regulated. Insights gained from this work may be applied to improving early childhood diseases affecting the intestines.
|Tsai, Yu-Hwai; Nattiv, Roy; Dedhia, Priya H et al. (2017) In vitro patterning of pluripotent stem cell-derived intestine recapitulates in vivo human development. Development 144:1045-1055|
|Dedhia, Priya H; Bertaux-Skeirik, Nina; Zavros, Yana et al. (2016) Organoid Models of Human Gastrointestinal Development and Disease. Gastroenterology 150:1098-1112|
|Tsai, Yu-Hwai; Hill, David R; Kumar, Namit et al. (2016) LGR4 and LGR5 Function Redundantly During Human Endoderm Differentiation. Cell Mol Gastroenterol Hepatol 2:648-662.e8|
|Taniguchi, Kenichiro; Shao, Yue; Townshend, Ryan F et al. (2015) Lumen Formation Is an Intrinsic Property of Isolated Human Pluripotent Stem Cells. Stem Cell Reports 5:954-962|
|Finkbeiner, Stacy R; Hill, David R; Altheim, Christopher H et al. (2015) Transcriptome-wide Analysis Reveals Hallmarks of Human Intestine Development and Maturation In Vitro and In Vivo. Stem Cell Reports :|
|Rodansky, Eva S; Johnson, Laura A; Huang, Sha et al. (2015) Intestinal organoids: a model of intestinal fibrosis for evaluating anti-fibrotic drugs. Exp Mol Pathol 98:346-51|
|Leslie, Jhansi L; Huang, Sha; Opp, Judith S et al. (2015) Persistence and toxin production by Clostridium difficile within human intestinal organoids result in disruption of epithelial paracellular barrier function. Infect Immun 83:138-45|
|Dye, Briana R; Hill, David R; Ferguson, Michael A H et al. (2015) In vitro generation of human pluripotent stem cell derived lung organoids. Elife 4:|
|Finkbeiner, Stacy R; Freeman, Jennifer J; Wieck, Minna M et al. (2015) Generation of tissue-engineered small intestine using embryonic stem cell-derived human intestinal organoids. Biol Open 4:1462-72|
|Zhang, Huabing; Ramakrishnan, Sadeesh K; Triner, Daniel et al. (2015) Tumor-selective proteotoxicity of verteporfin inhibits colon cancer progression independently of YAP1. Sci Signal 8:ra98|
Showing the most recent 10 out of 20 publications