VITAMIN A DEFICIENCY AND INTESTINAL MOTILITY DISORDERS

维生素 A 缺乏和肠蠕动障碍

• 批准号: 8776018
• 负责人: ROBERT O HEUCKEROTH
• 金额: $ 27.88万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8776018
• 关键词: VITAMIN; DEFICIENCY; INTESTINAL; MOTILITY; DISORDERS

DESCRIPTION (provided by applicant): The enteric nervous system (ENS) is a complex network of neurons and glia within the bowel wall that controls most aspects of bowel function. Defects in ENS development cause diverse intestinal motility problems including Hirschsprung disease, a problem where the ENS is missing from the end of the bowel. Problems with bowel motility and sensation are also primary characteristics of irritable bowel syndrome. Although Hirschsprung disease is a genetic disorder, new evidence from our laboratory demonstrate that vitamin A deficiency inhibits normal ENS development and predisposes to distal bowel aganglionosis in a mouse model system. We now hypothesize that even mild "subclinical" vitamin A deficiency will increase the risk of Hirschsprung disease in a genetically susceptible infant. If this is correct, then some cases of Hirschsprung disease, and perhaps other intestinal motility disorders, might be prevented by optimizing maternal nutrition. Studies in this proposal will validate this hypothesis in a murine model system, determine which cells depend on vitamin A metabolites for normal ENS development, and test the mechanistic hypothesis that retinoids facilitate ENS precursor migration by reducing Pten accumulation.

描述（由申请人提供）：肠神经系统（ENS）是肠壁内神经元和神经胶质细胞的复杂网络，控制着肠道功能的大部分方面。 ENS 发育缺陷会导致多种肠道蠕动问题，包括先天性巨结肠症，即肠末端 ENS 缺失的问题。肠蠕动和感觉问题也是肠易激综合征的主要特征。尽管先天性巨结肠症是一种遗传性疾病，但我们实验室的新证据表明，维生素 A 缺乏会抑制正常的 ENS 发育，并在小鼠模型系统中诱发远端肠神经节缺失。我们现在假设，即使是轻微的“亚临床”维生素 A 缺乏也会增加遗传易感婴儿患先天性巨结肠症的风险。如果这是正确的，那么某些先天性巨结肠症以及其他肠道动力障碍的病例可以通过优化孕产妇营养来预防。该提案中的研究将在小鼠模型系统中验证这一假设，确定哪些细胞依赖维生素 A 代谢物来正常 ENS 发育，并测试类视黄醇通过减少 Pten 积累促进 ENS 前体迁移的机制假设。

项目成果

Enteric nervous system development: migration, differentiation, and disease.

• DOI: 10.1152/ajpgi.00452.2012
• 发表时间: 2013-07-01
• 期刊: American journal of physiology. Gastrointestinal and liver physiology
• 作者: Lake JI;Heuckeroth RO
• 通讯作者: Heuckeroth RO