Wnt/PCP Signaling in the Intestinal Epithelium

描述(由申请者提供)：这份NIDDK导师研究科学家发展奖申请表描述了一项为期5年的培训计划，旨在让我获得更多的技能和知识，以便我可以过渡到一名由R01资助的独立终身教职研究科学家。在执行拟议的研究和职业发展计划时，我将增加我的科学技能，并获得肠道发育生物学方面的专业知识。利用这些新获得的专业知识，我将建立一个科学利基，使我有别于 我的导师，并为一个强大的，外部资助的研究计划铺平了道路。我设计了一个研究项目，利用我丰富的专业知识和非洲爪哇胚胎学的强大实验优势，以及独特的人类肠道器官(HIO)系统，从ES/iPS细胞诱导而来，这是CCHMC的一项首创技术。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)信号如何调节肠上皮的根尖基底极性(ABP)，并控制放射状-嵌入性和肠道伸长。具体地说，目标1将确定PCP途径调节非洲爪哇胎儿肠道上皮ABP和形态发生的机制。目的2研究人类肠道上皮细胞的体外发育特征，并验证ABP蛋白的Wnt/PCP调控在人类体内控制这一过程的假说。与NIDDK促进胃肠道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胃肠道畸形的理解，先天性胃肠道畸形发生在约0.2%的新生儿中，包括肠道旋转异常、短肠综合征或未能维持肠道组织完整性。这一提议产生的结果对人类疾病具有直接影响，因为它将为如何建立、维持和调节初始极性提供新的见解。这一知识可应用于旨在治疗影响胎儿肠道的消化系统疾病的再生疗法，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.