Gastroesophageal reflux disease (GERD) and Barrett's esophagus (BE), which are exceptionally common disorders in Veteran patients, are strong risk factors for esophageal adenocarcinoma. The frequency of BE-associated adenocarcinoma has increased more than six-fold in the past few decades, but the development of therapies to prevent this lethal tumor has been hampered by limited understanding of the molecular events underlying the pathogenesis and neoplastic progression of BE. We have preliminary data showing that Barrett's epithelial cells are more resistant to apoptosis induced by deoxycholic acid (DCA), a hydrophobic bile acid found in refluxed gastric juice, than the squamous cells that normally line the esophagus. Such apoptotic resistance might underlie the pathogenesis and persistence of Barrett's metaplasia, as esophageal squamous cells that succumb to bile acid-induced apoptosis are replaced by apoptosis-resistant Barrett's cells. Hydrophobic bile acids like DCA also have been shown to cause DNA damage, and extensive DNA damage normally triggers apoptosis. However, our preliminary data show that Barrett's cells respond to bile acid-induced DNA damage by activating anti-apoptotic survival pathways. This could facilitate the neoplastic progression of Barrett's metaplasia by allowing the survival of cells that have sustained cancer-promoting mutations. Moreover, our preliminary studies suggest that esophageal squamous cells from patients with BE may be more susceptible to apoptosis induced by DNA damage than esophageal squamous cells from GERD patients without BE. This predisposition of esophageal squamous cells to succumb to apoptosis also may contribute to the development of BE. Our preliminary data suggest that the NF-:B pathway plays a key role in the apoptotic resistance of Barrett's metaplasia. In addition, we have preliminary data showing that ursodeoxycholic acid (UDCA), a hydrophilic bile acid, does not induce genotoxic damage in Barrett's cells, and even protects against the DNA damage caused by DCA exposure. These findings suggest a potential chemopreventive role for UDCA. Based on our in vitro studies, we hypothesize that bile acids influence apoptosis in esophageal cells through effects on the NF-:B pathway. We now propose clinical investigations to determine whether our in vitro findings apply to patients with BE. The objectives of this study are to delineate the effects of esophageal bile acid perfusion on DNA damage, on the NF-:B pathway, and on apoptosis in esophageal squamous and metaplastic Barrett's epithelia in patients and, in those same patients, to determine the effects of altering bile acid composition with UDCA on DNA injury and NF-:B pathway proteins.
Project Narrative The Potential Impact on Veterans Health Care is the identification of specific molecular pathways that can be targeted to prevent the development and neoplastic progression of Barrett's esophagus in our veteran patients.
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