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: 2013
• 资助国家: 加拿大
• 起止时间: 2013-01-01 至 2014-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=527575
• 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.

肠道神经系统是周围神经系统中最大、最复杂的部分。它遍布整个肠道，负责正常的肠道运动。因此，ENS的异常发育是无神经节细胞巨结肠等肠道运动障碍的主要原因。这种致命的情况是由于肠道末端缺乏完整的ENS；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导致了对ENS发展至关重要的几个基因的识别。然而，鉴于神经内窥镜的复杂性，我们对其形成的理解还远远不完整。为了确定对ENS发育具有重要意义的新基因/基因座，我在转基因小鼠中进行了插入突变筛选。由于转基因随机插入到小鼠基因组中，这一屏幕允许识别出三个小鼠品系，命名为“DApple”、“优势斑点”和“荷斯坦”，它们表现出无神经节细胞的大结肠表型。到目前为止的遗传学研究表明，至少DApple和显性斑点的突变存在于新的基因/位点中。拟议的研究计划旨在识别和表征受这些突变影响的基因，特别是DApple品系。到目前为止的分子研究表明，新基因Kiaa1279的表达减少是导致DApple巨克隆表型的原因。在这方面，我现在建议进行研究，以了解Kiaa1279基因产物在ENS发育中的功能。总体而言，这项研究计划将大大扩展目前在遗传、分子和细胞水平上关于ENS发展的有限知识。这一新知识将对加拿大目前正在研究的一个重要研究领域作出重大贡献。