Duodenal Muscosal Defense Mechanisms

描述(申请人提供)：消化性溃疡疾病是老年人和慢性病患者发病率和死亡率的主要原因。尽管 消化性溃疡的发病机制及并发症研究进展 在高危人群中仍然是一个严重的问题，特别是在 老年人和患有严重并存疾病的人。消化性溃疡代表 攻击性因子(酸和胃酶)之间的平衡失调 防御因素(粘膜碳酸氢盐分泌、血流和粘液 分泌物)。其中，碳酸氢盐的分泌被认为是主要的防御措施。 机制，主要是由于碳酸氢盐分泌相关的研究 为了预防伤害，因为一般来说，碳酸氢盐分泌增加 保护粘膜免受酸引起的损伤。然而，准确的手段是 像十二指肠这样的固有渗漏的上皮可以通过它来抵抗 强酸性胃液造成的损害仍未解决。 在过去的几年里，我的实验室进行了一项新颖的观察， 提供了独特的洞察十二指肠绒毛上皮细胞是如何 针对胃酸，可抵抗损伤。我们制定了“细胞内” HCO3假说，细胞内，而不是细胞外碳酸氢盐提供服务 作为十二指肠黏膜的主要防御机制。为了检验这一假设， 我们设计了一系列实验，旨在将重碳酸盐“解偶联” 分泌物和粘膜保护。患有囊性纤维症的受试者， 尽管有大量的胃酸分泌和较低的十二指肠pH值，但很少有 十二指肠溃疡。我们认为这是重碳酸盐被困住的结果 在十二指肠上皮细胞中。我们计划直接在老鼠身上测试这一假设。 缺乏CFTR或囊性纤维化基因产物。通过…的行为 通过这些研究，我们希望对消化性疾病的发病机制有进一步的了解。 溃疡，希望找到新的治疗方法来预防溃疡 我们老龄化人口中的复杂情况，并获得对 囊性纤维化的发病机制。

DESCRIPTION (provided by applicant): Peptic ulcer disease is a major cause of morbidity and mortality in elderly and chronically ill populations. Despite major advances made about ulcer pathogenesis, complications of peptic ulcers still represent a significant problem in at-risk populations, especially in the elderly and those with significant co-morbidities. Peptic ulceration represents a disturbance in the balance between aggressive factors (acid and pepsin) and defensive factors (mucosal bicarbonate secretion, blood flow, and mucus secretion). Of these, bicarbonate secretion is thought to be a primary defense mechanisms, due mainly to studies in which bicarbonate secretion is correlated to injury prevention, since, in general, increased bicarbonate secretion protects the mucosa from acid-induced injury. Nevertheless, the precise means by which an intrinsically leaky epithelium such as the duodenum can resist damage from intensely acid gastric juice remains unresolved. In the past few years, my laboratory has made the novel observation that provides unique insight into how duodenal villus epithelial cells, the prime targets of gastric acid, can resist injury. We formulated the 'intracellular HCO3' hypothesis in which intracellular, not extracellular bicarbonate serves as the principal duodenal mucosal defense mechanism. To test this hypothesis, we have devised a series of experiments designed to 'uncouple' bicarbonate secretion and mucosal protection. Subjects with the disease cystic fibrosis, despite copious gastric acid secretion and low duodenal pH, only rarely have duodenal ulcers. We believe that this is a result of bicarbonate being trapped in duodenal epithelial cells. We plan to test this hypothesis directly in mice deficient for the CFTR or cystic fibrosis gene product. Through the conduct of these studies, we hope to gain further insight into the mechanism of peptic ulceration, in the hopes of finding new treatments designed to prevent ulcer complications in our aging population, and to also gain additional insight into the pathogenesis of cystic fibrosis.