VITAMIN A DEFICIENCY AND INTESTINAL MOTILITY DISORDERS

描述(申请人提供)：肠神经系统(ENS)是肠壁内由神经元和神经胶质细胞组成的复杂网络，控制着肠道功能的大部分方面。ENS发育缺陷会导致包括先天性巨结肠在内的各种肠道运动问题，这是一种从肠道末端缺失ENS的问题。肠动力和感觉问题也是肠易激综合征的主要特征。虽然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，在小鼠模型系统中，维生素A缺乏抑制了正常的ENS发育，并易患上远端肠道无神经节细胞增多症。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的风险。如果这是正确的，那么一些先天性巨结肠病例，也许还有其他肠道动力障碍，可能会通过优化母亲的营养来预防。这项建议中的研究将在小鼠模型系统中验证这一假说，确定哪些细胞依赖维生素A代谢物来正常发育ENS，并测试维甲酸通过减少Pten积累促进ENS前体迁移的机制假说。

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.