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 to an independent R01-funded tenure track research scientist. In carrying out the proposed research and career development plan, I will add to my scientific repertoire and acquire expertise in intestinal developmental biology. Using this newly acquired expertise I will establish a scientific niche that will set me apart from my mentor and pave the way to a robust, extramurally funded research program. I have designed a research program that leverages my extensive expertise with the powerful experimental advantages of Xenopus embryology coupled with unique human intestinal organoids (HIOs) system, induced from ES/iPS cells, a technique pioneered here at CCHMC.
The specific aims are designed to test how Wnt/Planar Cell Polarity (PCP) signaling between lateral plate mesoderm (LPM) and endoderm regulates apicobasal polarity (ABP) of intestinal epithelium and controls radial---intercalation and gut elongation. Specifically, Aim 1 will determine the mechanisms by which the PCP pathway regulates ABP and morphogenesis in the Xenopus fetal gut epithelium.
Aim 2 will characterize human intestinal epithelial development in vitro and test the hypothesis that Wnt/PCP regulation of ABP proteins controls this process in humans. Consistent with the NIDDK's strategic plan of promoting gastrointestinal (GI) organogenesis studies to advance human health, my research will impact our understanding of congenital GI malformation, which occur in ~0.2% of newborns, and include abnormal gut rotation, short gut syndrome or failure to maintain intestinal tissue integrit. The results generated by this proposal have direct implications for human disease, since it will provide new insights into how initial polarity is established, maintained and regulated. This knowledge may be applied to regenerative therapies aimed at treating digestive disease affecting the fetal intestine, such as inflammatory bowel disease and short bowel syndrome.
Diseases that affect the perinatal digestive tract include inflammatory bowel disease and short bowel syndrome, and lead to increased rates of mortality and morbidity in preterm infants. In most cases the etiology of these defects are unknown but they are likely to be influenced by morphogenesis of the fetal GI epithelium during embryogenesis. The goal of this proposal is to better understand the molecular and cellular basis that controls development of the intestinal epithelium. To do this we uses the innovative experimental approach of combining experimental advantages of an vertebrate model, the frog Xenopus, which has a gut like humans, together with the recent technology where we can generate human intestinal tissue in a petri dish from stem cells. The results of our research will have a broad and significant impact on our understanding of human intestinal disease, and may reveal potential pathogenic and therapeutic targets. Insights gained from this work may lead to improved outcomes for early childhood intestinal diseases. Finally, my studies may have a broad impact on the development and disease of different epithelial tissues in many contexts.