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，并测试类维生素A通过减少 Pten 积累促进 ENS 前体迁移的机制假设。 公众健康相关性：肠动力障碍很常见，使人衰弱且难以治疗。根据新数据，我们现在认为，轻度“亚临床”维生素 A 缺乏是这些疾病的危险因素，包括先天性巨结肠症，这是一种肠壁内神经系统（即肠神经系统）从肠末端完全缺失的问题。这些研究旨在寻找预防先天性巨结肠症和其他肠道动力障碍的新方法。

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. PUBLIC HEALTH RELEVANCE: Intestinal motility disorders are common, debilitating and difficult to treat. Based on new data we now believe that mild "subclinical" vitamin A deficiency is a risk factor for these disorders including Hirschsprung disease, a problem where the nervous system within the bowel wall (i.e., the enteric nervous system) is completely missing from the end of the bowel. These studies are designed to find new ways to prevent Hirschsprung disease and other intestinal motility disorders.