DUODENAL MUCOSAL BICARBONATE SECRETION

十二指肠溃疡(DU)在美国仍然是一个主要的卫生保健问题。 各州每年新增病例约50万例，溃疡复发约400万例 每年，总成本超过250亿美元/耳。由于根除了 幽门螺杆菌(HP)可显著减少DU的复发；它是 假设复发率会相应降低。十二指肠 球茎是胃酸中和和消化的熔炉。 活动已停用。我们观察到大多数DU患者 (约80%)十二指肠近端碳酸氢盐分泌减少(DMBS)和 根除十二指肠溃疡的幽门螺杆菌使原来受损的十二指肠恢复正常 碱性分泌物。DMBS是粘膜防御中的一个关键过程 “粘液/碳酸氢盐屏障”)；并且，当显著减少时，会导致 粘膜损伤。 这一紧密结合的提案将提供临床上相关的 以及有关十二指肠上皮HCO3的基本信息 运输。我们将确定导致下降的机制(S) 系统探讨幽门螺杆菌感染DU患者的DMBS 体内和体外转运事件的调节。DMBS将是 在根除幽门螺杆菌之前和之后定期研究 确定根除幽门螺杆菌后DMBS的恢复是否为次要的 对生物体(或特定的同源突变体)、炎性细胞因子或 寄主因素。ALS，人[DU(Hp+和-)和正常(NL，也称为Hp+和- 分离十二指肠近端肠上皮细胞，负载BCECF/AM， 鉴定了酸/碱转运体并测定了它们的动力学。 形成了鲜明对比。定位(根尖VS基底侧)和相对 十二指肠转运体对上皮酸/碱运动的作用 将定义在标准使用小室(兔)以及一个新的微型 接受人类十二指肠活组织检查的小室。因此，负责的事件 对于人类(DU和NL)，将在有膜的完整组织中探索DMBS 两极。此外，顶端阴离子(CI多于HCO3)的作用 将定义碱性分泌物中的电导(S)。我们还将 识别和探索独特的递减模型中的调控因素 DMBS，纯合子转基因囊性纤维化小鼠。 因此，带着仔细聚焦的问题，结合 测试模型(人-兔-鼠的产量)和方法(体内 在体外产生组织产生分离的十二指肠细胞)，这将是可能的 确定在疾病中改变DMBS的事件(例如，DU和囊性 纤维化)以及确定基本的调控过程。

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.