GI Mucosal Barrier in Health and Surgical Disease

描述（由申请人提供）： 这项工作的总体目标是了解幽门螺杆菌（HP）感染如何导致胃粘膜损伤，特别强调胃的胃底区域。 研究人员计划研究HP感染如何损害紧密连接的完整性和损伤后的伤口修复（恢复），从而导致粘膜通透性增加。 HP诱导的胃粘膜损伤很重要，因为它是HP疾病发病机制的主要起始因素，包括炎症、胃底上皮细胞（包括壁细胞和主细胞）萎缩、化生和进展为胃癌。 由于HP感染在良性和恶性疾病方面具有深远的影响，因此粘膜损伤的启动、损伤后的修复和保护免受损伤的机制是重要和及时的。 将检验三个假设。 1)HP感染增加了粘膜通透性，因为HP或炎性细胞降低了紧密连接的完整性。 这一假设将通过研究如何HP超声或细胞因子分泌的1型辅助性T细胞（Th 1）反应影响磷酸化和膜的紧密连接相关的蛋白质的协会进行测试。 2)HP感染增加粘膜通透性，因为HP感染期间产生的细胞毒素氨抑制恢复。 将通过研究氨对H+/乳酸转运蛋白（MCT 1）活性和基底外侧K+通道活性的影响来检验这一假设。 3)补充L-谷氨酰胺（Gln）通过抑制Th 1应答和HP感染期间发生的谷氨酰胺诱导的紧密连接完整性降低来降低粘膜通透性。 将通过确定L-Gln补充是否抑制Th 1细胞因子应答以保持疾病小鼠模型中紧密连接的完整性来检验该假设。 拟议的调查遵循本实验室以前研究的逻辑顺序，这些研究为我们了解粘膜损伤、保护免受损伤和快速上皮修复（恢复）提供了结构框架，因为它们与健康和手术疾病中胃粘膜屏障的维持有关。

DESCRIPTION (provided by applicant): The overall aim of the proposed work is to understand how Helicobacter pylori (HP) infection causes mucosal damage in the stomach, with special emphasis on the fundic region of the stomach. The investigators plan to study how HP infection impairs tight junction integrity and wound repair after injury (restitution) to result in increased mucosal permeability. HP-induced mucosal damage of the stomach is important because it is a major initiating factor in the pathogenesis of HP disease, including inflammation, atrophy of fundic epithelial cells including parietal and chief cells, metaplasia, and progression to gastric cancer. Because HP infection has far-reaching implications in terms of benign and malignant disease, mechanisms that underlie the initiation of mucosal damage, repair after damage, and protection against damage are important and timely. Three hypotheses will be tested. 1) HP infection increases mucosal permeability because either HP or inflammatory cells decrease tight junction integrity. This hypothesis will be tested by investigating how HP sonicates or cytokines secreted during a type 1 T-helper (Th1) response affect the phosphorylation and membrane association of proteins associated with the tight junction. 2) HP infection increases mucosal permeability because ammonia, a cytotoxin produced during HP infection, inhibits restitution. This hypothesis will be tested by investigating the effects of ammonia on activity of the H+/lactate transporter, MCT1, and on basolateral K+-channel activity. 3) L-glutamine (Gln) supplementation decreases mucosal permeability by inhibiting the Th1 response and cytokine-induced decreases in tight junction integrity that occur during HP infection. This hypothesis will be tested by determining whether L-Gln supplementation inhibits the Th1 cytokine response to preserve tight junction integrity in a mouse model of disease. The proposed investigations follow a logical sequence from previous studies in this laboratory, which have provided a structural framework for our knowledge of mucosal injury, protection against injury, and rapid epithelial repair (restitution) as they relate to maintenance of the gastric mucosal barrier in health and surgical disease.