Duodenal Muscosal Defense Mechanisms

描述（由申请人提供）：消化性溃疡疾病是 老年人和慢性病患者的发病率和死亡率。尽管 消化性溃疡的发病机制、并发症及治疗进展 在高危人群中仍然是一个严重的问题，特别是在 老年人和有显著合并症的人。消化性溃疡代表 侵蚀性因素（酸和胃蛋白酶）之间的平衡紊乱， 防御因素（粘膜碳酸氢盐分泌、血流和粘液 分泌）。其中，碳酸氢盐分泌被认为是一种主要的防御 机制，主要是由于研究中，碳酸氢盐分泌相关 伤害预防，因为，一般来说，增加碳酸氢盐分泌 保护粘膜免受酸诱导的损伤。然而，精确的方法 通过该方法，诸如十二指肠的固有渗漏上皮可以抵抗 强酸胃液造成的损害仍未得到解决。 在过去的几年里，我的实验室进行了新的观察， 提供了独特的见解，如何十二指肠绒毛上皮细胞，主要 目标胃酸，可以抵抗伤害。我们制定了“细胞内 HCO3'假说，其中细胞内，而不是细胞外的碳酸氢盐 作为主要的十二指肠粘膜防御机制。为了验证这个假设， 我们设计了一系列实验， 分泌和粘膜保护。患有囊性纤维化疾病的受试者， 尽管有大量胃酸分泌和低十二指肠pH值， 十二指肠溃疡我们认为这是由于碳酸氢盐 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。通过开展 通过这些研究，我们希望能进一步了解消化道疾病的机制， 溃疡，希望找到新的治疗方法，旨在防止溃疡 并发症在我们的老龄化人口，并获得额外的洞察力， 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.