Development of the enteric nervous system

肠神经系统是周围神经系统中最大和最复杂的部分。它存在于整个肠道的长度，并负责正常的肠道运动。因此，ENS的异常发育是肠动力障碍如无神经节巨结肠的主要原因。这种致命的疾病是由于肠道末端区域缺乏完整的ENS造成的;受影响的部分保持收缩，导致肠梗阻，扩张和严重便秘。人类临床病例和动物模型已导致对ENS发育重要的几个基因的鉴定。然而，由于ENS的复杂性，我们对其形成的理解还远远不够。为了鉴定对ENS发育重要的新基因/位点，我在转基因小鼠中进行了插入突变筛选。由于转基因在小鼠基因组中的随机插入，该筛选允许鉴定三个品系的小鼠，命名为“Dapple”、“Dominant Spot”和“Holstein”，其显示无神经节巨结肠表型。迄今为止的遗传学研究表明，至少斑点和显性斑点的突变是在新的基因/基因座中。拟议的研究计划旨在识别和表征受这些突变影响的基因，特别关注Dapple系。迄今为止的分子研究表明，新基因Kiaa 1279的表达减少是Dapple巨结肠表型的原因。在这方面，我现在建议的研究，以了解在ENS发展的Kiaa 1279基因产物的功能。总的来说，这项研究计划将显着扩大目前有限的知识ENS发展在遗传，分子和细胞水平。这些新知识将对加拿大目前研究不足的一个重要研究领域作出重要贡献。

The enteric nervous system is the largest and most complex part of the peripheral nervous system. It is found throughout the length of the intestines and is responsible for normal bowel motility. Thus, abnormal development of the ENS is the main cause of gut motility disorders such as aganglionic megacolon. This lethal condition is caused by the absence of an intact ENS in the terminal regions of the gut; the affected segment stays contracted leading to intestinal obstruction, dilation and severe constipation. Human clinical cases and animal models have led to the identification of several genes important for ENS development. Nevertheless, given the complexity of the ENS, our understanding of its formation is far from complete. In order to identify new genes/loci important for ENS development, I have performed an insertional mutation screens in transgenic mice. Due to random insertion of transgenes in the mouse genome, this screen allowed the identification of three lines of mice, named "Dapple", "Dominant Spot" and "Holstein" that display an aganglionic megacolon phenotype. Genetic studies to date have shown that at least the mutations for Dapple and Dominant Spot are in new genes/loci. The proposed research program is aimed at identifying and characterizing the genes affected by these mutations with a special focus on the Dapple line. Molecular studies to date suggest that reduced expression of the new gene Kiaa1279 is responsible of the Dapple megacolon phenotype. In this regard, I now propose studies to understand the function of the Kiaa1279 gene product in ENS development. Overall, this research program will significantly expand the current limited knowledge of ENS development at the genetic, molecular and cellular levels. This new knowledge will represent key contributions to an important research field which is currently understudied in Canada.