Biological and Mathematical Studies of Development of the Enteric Nervous System

在胚胎非常早期的发育过程中，细胞从未来的大脑迁移过来。这些细胞被称为神经嵴细胞，它们通向肠道最近的部分，也就是未来的食道。然后随着数量的增加，它们沿着肠道迁移，直到它们占据了整个肠道，一直到直肠。更复杂的是，随着这种迁移的发生，肠道本身也在沿着长度方向快速增长。这些神经嵴细胞形成了肠道内的神经细胞，控制肠道功能。在一种常见的先天性缺陷——先天性巨结肠病中，这种迁移在直肠之前就停止了，因此肠道的最后一部分永远不会发育出神经细胞。这个区域缺乏神经细胞，不能推动肠道内容物，如果不治疗，这种顽固性便秘在出生后是致命的。8个基因发生突变后，无论在人类还是动物身上，都会产生基本相同的病症，但这些基因与病症之间的联系仍不清楚。我们提出，基因编码的分子影响神经嵴细胞与其他神经嵴细胞和肠道细胞相互作用的方式，其中迁移发生。基因与正常肠道神经系统的发育（或其故障，如巨结肠病）之间的联系在神经嵴细胞群的动态水平上运作，与肠道生长的动态相互作用。该项目将使用非常详细的生物学数据采集来输入新制定的原始数学模型，以梳理神经嵴细胞群和生长中的肠道之间的重要联系，控制细胞迁移。这将导致对肠道神经系统和巨结肠病形成的理解，在人口水平上，这是分子水平上无法很好地理解的。这些模型将在许多细胞运动和生长同时发生的发育环境中得到应用。

During very early development in the embryo, cells migrate from the future brain. These cells, called neural crest cells, make there way to the nearest part of the gut, in the future oesophagus. They then migrate as a growing population right along the gut until they have populated the entire gut down to the rectum. To complicate matters, the gut itself is rapidly growing length-wise as this migration occurs. These neural crest cells then form the nerve cells that reside in the gut and which control gut function. In a common birth defect, Hirschsprung's disease, this migration stops short of the rectum so that the last part of the gut never develops nerve cells. This region lacking nerve cells is unable to propel the gut contents and, if untreated, this condition of intractable constipation is fatal after birth. Eight genes, when mutated, give essentially the same condition either in humans or animals, but the link between the genes and the condition is still not clear. We have proposed that the genes code for molecules that effect the way the neural crest cells interact with other neural crest cells and with the cells of the gut in which migration takes place. The link between the genes and the development of a normal gut nerve system (or its failure, as in Hirschsprung's disease) operates at the level of the dynamics of the neural crest cell population, interacting with the dynamics of gut growth. This project will use very detailed biological data acquisition to feed into newly formulated original mathematical models to tease out the important links between the neural crest cell population and the growing gut, that control cell migration. This will lead to an understanding of formation of the gut nerve system and of Hirschsprung's disease, at the population level, a level not well served by molecular levels of understanding. These models will have application in the many developmental contexts where cell movement and growth are simultaneous.