DUODENAL MUCOSAL BICARBONATE SECRETION

十二指肠粘膜碳酸氢盐分泌

• 批准号: 2458739
• 负责人: JON I ISENBERG
• 金额: $ 36.9万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 1984
• 资助国家: 美国
• 起止时间: 1984-12-01 至 2000-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2458739
• 关键词: Helicobacter; acidity /alkalinity; apical membrane; basolateral membrane; bicarbonates; biopsy; brush border membrane; calcium; cellular polarity; clinical research; cystic fibrosis; cytokine; duodenal ulcer; duodenum; endoscopy; gastrointestinal infection; histamine; human subject; inflammation; intestinal mucosa; ion transport; laboratory rabbit; membrane channels; membrane transport proteins; secretion

Duodenal ulcer (DU) remains a major health care problem in the United States with about 0.5 M new cases year, about 4 M ulcer recurrences annually, and a total cost of more than $25 B/hear. As eradication of Helicobacter pylori (HP) distinctly diminishes DU recurrences; it is presumed that the relapse rate will correspondingly decrease. The duodenal bulb is the crucible in which gastric acid is neutralized and peptic activity is inactivated. We observed that the majority of patients with DU (about 80%) have reduced proximal duodenal bicarbonate secretion (DMBS) and that eradication of HP in DU normalized the formerly impaired duodenal alkaline secretion. DMBS is a key process in mucosal defense (the "mucus/bicarbonate barrier"); and, when diminished significantly results in mucosal damage. This tightly integrated proposal will provide both clinically relevant as well as fundamental information regarding duodenal epithelial HCO3 transport. We shall identify the mechanism(s) responsible for decreased DMBS in DU patients infected with HP by systematically probing the regulation of transport events both in vivo and in vitro. DMBS will be studied prior to and at regular intervals after eradication of Hp to determine whether the restitution of DMBS after Hp eradication is secondary to the organism (or specific isogenic mutants), inflammatory cytokines or host factors. Als, human [DU (HP + and -) and normal (NL, also HP + and - )] proximal duodenal enterocytes will be isolated, loaded with BCECF/AM, acid/base transporters identified and their kinetics determined and contrasted. The localization (apical vs. basolateral) and relative functions of duodenal transporters that on epithelial acid/base movement will be defined in standard Ussing chamber (rabbit) as well as a new micro- chamber that accepts human duodenal biopsies. Thus, the events responsible for human (DU and NL) DMBS will be explored in intact tissue with membrane polarity. Moreover, the role of apical anion (CI more then HCO3) conductance(s) in alkaline secretion will be defined. We shall also identify and probe the regulatory factors in a unique model of decreased DMBS, homozygous transgenic cystic fibrosis mice. Thus, with carefully focused questions, combined with close integration of test models (human-yields to rabbit yields to mice) and methods (in vivo yields in vitro tissue yields isolated duodenocytes), it will be possible to identify the events that alter DMBS in disease (i.e., DU and cystic fibrosis) as well a identify the fundamental regulatory processes.

十二指肠溃疡（DU）仍然是美国的一个主要卫生保健问题， 美国每年约有50万新发病例，约有400万溃疡复发 每年，总成本超过25 B/hear。 作为根除 幽门螺杆菌（HP）明显减少DU复发;它是 假设复发率会相应降低。 十二指肠 灯泡是胃酸被中和和消化的坩埚 活动被取消。 我们观察到大多数DU患者 （约80%）减少了近端十二指肠碳酸氢盐分泌（DMBS）， 在DU中根除HP使先前受损的十二指肠恢复正常， 碱性分泌 DMBS是粘膜防御中的关键过程（ “粘液/碳酸氢盐屏障”）;并且，当显著减少时， 粘膜损伤 这一紧密整合的提案将提供临床相关的， 以及关于十二指肠上皮HCO 3的基本信息 运输 我们将确定减少的机制 系统探讨HP感染DU患者的DMBS 调节体内和体外的转运事件。 DMBS将在 在根除Hp之前和之后定期进行研究， 确定Hp根除后DMBS的恢复是否是继发性的 对生物体（或特定的同基因突变体）、炎性细胞因子或 宿主因素 Als，人[DU（HP +和-）和正常（NL，也是HP +和-）] 分离近端十二指肠上皮细胞，加载BCECF/AM， 确定酸/碱转运蛋白并测定其动力学， 对比。 定位（顶侧与基底侧）和相对 十二指肠转运蛋白对上皮细胞酸碱运动的作用 将在标准Ussing室（家兔）以及新的微- 接受人体十二指肠活检的腔室。 因此， 对于人（DU和NL），将在具有膜的完整组织中探索DMBS 极性 此外，顶端阴离子（Cl大于HCO 3） 将定义碱性分泌中的电导。 我们亦会 在一个独特的模型中识别和探测调节因子， DMBS，纯合子转基因囊性纤维化小鼠。 因此，通过仔细集中的问题，结合紧密结合的 测试模型（人-兔-小鼠）和方法（体内 产生体外组织产生分离的巨噬细胞）， 为了鉴定改变疾病中DMBS的事件（即，DU和囊性 纤维化）以及确定基本的调节过程。