Wnt/PCP Signaling in the Intestinal Epithelium

描述（由申请人提供）：此NIDDK指导研究科学家发展奖申请描述了一个为期5年的培训计划，旨在让我获得额外的技能和知识，使我可以过渡到一个独立的R 01资助的终身制研究科学家。在执行拟议的研究和职业发展计划，我将增加我的科学剧目，并获得在肠道发育生物学的专业知识。利用这一新获得的专业知识，我将建立一个科学的利基，这将使我除了 我的导师和铺平道路，一个强大的，校外资助的研究计划。我设计了一个研究计划，利用我丰富的专业知识，利用非洲爪蟾胚胎学的强大实验优势，结合独特的人类肠道类器官（HIOs）系统，从ES/iPS细胞诱导，这是CCHMC开创的一项技术。具体目的是测试侧板中胚层（LPM）和内胚层之间的Wnt/平面细胞极性（PCP）信号传导如何调节肠上皮的顶基极性（ABP）并控制径向嵌入和肠伸长。具体来说，目标1将确定PCP途径调节ABP和形态发生在爪蟾胎儿肠上皮细胞的机制。目的2将在体外表征人肠上皮发育，并测试ABP蛋白的Wnt/PCP调节控制这一过程的假设。与NIDDK促进胃肠道（GI）器官发生研究以促进人类健康的战略计划一致，我的研究将影响我们对先天性GI畸形的理解，这些畸形发生在约0.2%的新生儿中，包括异常肠道旋转，短肠综合征或未能维持肠组织完整性。这一提议产生的结果对人类疾病有直接影响，因为它将为初始极性如何建立、维持和调节提供新的见解。这些知识可以应用于再生疗法，旨在治疗影响胎儿肠道的消化系统疾病，如炎症性肠病和短肠综合征。

DESCRIPTION (provided by applicant): 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.