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Duodenal Muscosal Defense Mechanisms

十二指肠粘膜防御机制

基本信息

批准号：
6850669
负责人：
Jonathan D. Kaunitz
金额：
$ 30.84万
依托单位：
BRENTWOOD BIOMEDICAL RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
1999
资助国家：
美国
起止时间：
1999-05-01 至 2007-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6850669
关键词：
acid base balance bicarbonates cellular pathology chloride channels cytoprotection disease /disorder model duodenal ulcer duodenum fluorescence microscopy gastric acid gastrointestinal epithelium inflammation intestinal mucosa intravital microscopy laboratory mouse laboratory rat video microscopy

项目摘要

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.

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发病率和死亡率的主要原因。尽管