Neurogenin3 and Intestinal Failure

描述(由申请人提供)：一小部分儿童出生时患有严重威胁生命的腹泻，可归类为先天性腹泻，但比例很高。这些儿童经常患有越来越多的遗传性疾病之一，这些遗传性疾病通常会导致各种营养和盐分在肠道中的不正常运动。我们最近发现，一群无法吸收所有形式的营养的儿童患有遗传性疾病，导致无法形成肠道内分泌细胞。肠内分泌细胞是驻留在肠道中的产生激素的细胞，它们的形成是由一种名为Neurogenin3的基因驱动的，而这种基因在这些儿童中是有缺陷的。在这项拨款申请中，我们建议鉴定更多有神经原-3基因缺陷的儿童，以便我们能够更好地了解这种疾病的临床意义。我们也一直在研究携带神经原-3基因类似突变的小鼠，我们正在用它来分离小鼠和人类早期和晚期的肠道内分泌细胞。一个主要的目标是分离这些细胞，这样我们就可以更好地了解它们是如何工作的，以及这些细胞的亚群是如何发育的。我们还发现，神经生长素-3使在实验室培养的肠内分泌细胞停止分裂，并呈现成熟肠内分泌细胞的特征。我们希望了解神经原蛋白-3如何导致细胞停止分裂的机制，并确定类似的过程是否发生在活着的小鼠身上。最后，我们有证据表明，肠道内分泌细胞的丧失会导致负责吸收营养的肠道细胞(称为肠细胞)功能障碍。在这里，我们计划进行一系列实验，以开始了解缺乏肠内分泌细胞如何导致肠细胞对营养物质的不当处理的机制。与公共卫生相关：出生后不久就出现慢性腹泻的儿童死亡率很高，这些情况还没有得到很好的了解。我们最近发现了一种新的疾病，导致先天性腹泻，这是由于未能发育肠道激素产生细胞所致。在这项拨款中，我们建议进行实验，以更密切地检查这组人和老鼠(具有相同的条件)。随着这些目标的完成，我们预计将进一步分析这种疾病的生理基础，并进一步阐明这种疾病中存在缺陷的基因(Neurogenin-3)如何导致肠道内分泌细胞发育和功能的机制。我们相信，这些研究将为如何改善这些患者的营养吸收提供新的策略，并在健康方面更全面地了解这一过程。

DESCRIPTION (provided by applicant): A small but significant percentage of children are born with severe life threatening diarrhea that can be classified as congenital. These children frequently have one of a growing group of genetic disorders that generally result in improper movement of various nutrients and salts across the intestine. We have recently discovered that a group of children who are incapable to absorbing all forms of nutrients have a genetic disorder that results in the inability to form enteroendocrine cells. Enteroendocrine cells are the hormone producing cells that reside in the gut and their formation is driven by a gene named Neurogenin3 that is defective in these children. In this grant application, we propose to identify more children with defects in the NEUROGENIN-3 gene so that we can get a better understanding of the clinical implications of this disorder. We also have been working on mice that carry a similar mutation of the NEUROGENIN-3 gene and we're using it to isolate the early and late forms of enteroendocrine cells in mice and humans. One main goal is to isolate these cells is so that we can get a better understanding of how they work, and how subsets of these cells develop. We have also found that NEUROGENIN-3 causes enteroendocrine cells that are grown in the laboratory to stop dividing and to take on the characteristics of mature enteroendocrine cells. We hope to understand the mechanism of how NEUROGENIN-3 causes the cells to stop dividing and to determine if a similar process is occurring in live mice. Finally, we have evidence that a loss of enteroendocrine cells results in a dysfunction of the intestinal cells called enterocytes that are responsible for absorbing nutrients. Here we plan a series of experiments to begin understanding the mechanism of how an absence of enteroendocrine cells leads to improper handling of nutrients by the enterocytes. PUBLIC HEALTH RELEVANCE: Children that develop chronic diarrhea shortly after birth have a very high mortality rate and these conditions are not well understood. We have recently discovered a new disorder that results in congenital diarrhea that occurs from the failure to develop gut hormone producing cells. In this grant we propose experiments to examine this group of humans and mice (with an identical condition) more closely. At the completion of these aims, we anticipate having further analyzed the physiologic basis of this disorder and will have further elucidated the mechanism of how the gene that is defective in this disorder (NEUROGENIN-3) causes gut endocrine cells to develop and function. We believe that these studies will provide new strategies of how to improve nutrient absorption in these patients and to understand this process more fully in health.