Neurogenin3 and Intestinal Failure

Neurogenin3 和肠衰竭

• 批准号: 7742655
• 负责人: MARTIN G MARTIN
• 金额: $ 36.96万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7742655
• 关键词: Ablation; Adult; Alpha-mannosidase; Apical; Applications Grants; Assimilations; Birth; Brush Border; Cell Cycle Arrest; Cell Differentiation process; Cell Line; Cell Proliferation; Cells; Characteristics; Child; Chronic; Clinical; Collection; Data; Defect; Development; Diarrhea; Diphtheria Toxin; Disease; Endocrine; Enhancers; Enteral; Enterocytes; Enteroendocrine Cell; Enzymes; Failure; Functional disorder; Genes; Germ-Line Mutation; Goals; Grant; Health; Helix-Loop-Helix Motifs; Hereditary Disease; Hormones; Human; Hybrids; Impairment; Intestinal Diseases; Intestines; Ions; Islet Cell; Knockout Mice; Laboratories; Life; Malabsorption Syndromes; Mediating; Molecular; Mouse Cell Line; Movement; Mus; Mutation; Names; Neonatal; Nutrient; Pancreas; Pathologic; Patients; Physiological; Process; Proteins; Role; Salts; Series; Stem cells; Stream; System; Testing; Work; Yeasts; absorption; apical membrane; attenuation; base; clinical phenotype; gut endocrine cell; improved; inhibitor/antagonist; insight; islet; migration; mortality; mouse Neurog3 protein; novel; public health relevance; research study; transcription factor; uptake

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.

描述（由申请人提供）：一小部分但很大比例的儿童出生时患有严重危及生命的腹泻，可归类为先天性腹泻。这些孩子经常有一个日益增长的遗传疾病，通常会导致各种营养物质和盐在肠道中的不正确运动。我们最近发现，一群无法吸收所有形式营养的儿童患有遗传疾病，导致无法形成肠内分泌细胞。肠内分泌细胞是存在于肠道中的激素产生细胞，它们的形成是由一种名为Neurogenin 3的基因驱动的，这种基因在这些儿童中是有缺陷的。在这项拨款申请中，我们建议识别更多的神经生成素-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生成素-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形式的肠内分泌细胞。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，神经生成素-3可使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。我们希望了解神经生成素-3如何导致细胞停止分裂的机制，并确定活小鼠中是否也发生了类似的过程。最后，我们有证据表明，肠内分泌细胞的损失导致肠道细胞（称为肠上皮细胞）功能障碍，肠上皮细胞负责吸收营养。在这里，我们计划进行一系列的实验，开始了解肠内分泌细胞的缺乏如何导致肠细胞对营养物质的不当处理的机制。公共卫生关系：出生后不久患上慢性腹泻的儿童死亡率非常高，这些情况尚未得到很好的了解。我们最近发现了一种新的疾病，导致先天性腹泻，发生从未能开发肠道激素产生细胞。在这项资助中，我们提出了更仔细地检查这组人类和小鼠（条件相同）的实验。在完成这些目标后，我们预计将进一步分析这种疾病的生理基础，并将进一步阐明这种疾病中有缺陷的基因（神经生成素-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，并更全面地了解健康状况下的这一过程。