Development of the enteric nervous system

肠神经系统的发育

• 批准号: 342093-2009
• 负责人: Pilon, Nicolas
• 金额: $ 2.91万
• 依托单位: Université du Québec à Montréal
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2012
• 资助国家: 加拿大
• 起止时间: 2012-01-01 至 2013-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=515149
• 关键词: Development; enteric; nervous; system

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.

肠神经系统是周围神经系统最大、最复杂的部分。它遍布整个肠道，负责正常的肠道蠕动。因此，ENS发育异常是无神经节巨结肠等肠道动力障碍的主要原因。这种致命的情况是由于肠道末端区域缺乏完整的 ENS 造成的。受影响的部分持续收缩，导致肠梗阻、扩张和严重便秘。人类临床病例和动物模型已鉴定出对 ENS 发育很重要的几个基因。然而，鉴于 ENS 的复杂性，我们对其形成的理解还远未完成。为了确定对 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，该筛选允许鉴定出显示无神经节巨结肠表型的三系小鼠，名为“Dapple”、“Dominant Spot”和“Holstein”。迄今为止的遗传学研究表明，至少斑纹和显性斑点的突变位于新基因/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 Kiaa1279 表达的减少是造成斑纹巨结肠表型的原因。在这方面，我现在提出研究以了解 Kiaa1279 基因产物在 ENS 发育中的功能。总体而言，该研究计划将在遗传、分子和细胞水平上显着扩展目前关于 ENS 发展的有限知识。这些新知识将代表对加拿大目前正在研究的一个重要研究领域的关键贡献。