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.
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