VITAMIN A DEFICIENCY AND INTESTINAL MOTILITY DISORDERS

描述（由申请人提供）：肠神经系统（ENS）是肠壁内由神经元和胶质细胞组成的复杂网络，控制着肠功能的大多数方面。肠系系统发育缺陷会导致多种肠道运动问题，包括先天性巨结肠病，即肠末端的肠系系统缺失。肠蠕动和感觉问题也是肠易激综合征的主要特征。虽然巨结肠病是一种遗传性疾病，但我们实验室的新证据表明，在小鼠模型系统中，维生素a缺乏会抑制正常的ENS发育，并容易发生远端肠神经节病。我们现在假设，即使是轻微的“亚临床”维生素A缺乏也会增加基因易感婴儿患巨结肠疾病的风险。如果这是正确的，那么一些巨结肠疾病，也许还有其他肠道运动障碍，可以通过优化母体营养来预防。本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，并测试类维生素a通过减少Pten积累促进ENS前体迁移的机制假设。

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.