The major objective of our studies is to understand the molecular changes that occur in response to acid and bile exposure in normal and Barrett's esophagus (BE). BE is a metaplastic premalignant condition of the esophagus that is associated with an increased risk of up to 30-fold of developing esophageal adenocarcinoma. Exposure of the esophagus to the duodeno-gastro-esophageal (DGE) refluxate, important constituents of which include acid and bile, is a major risk factor for the development of BE and subsequent esophageal adenocarcinoma. Our overall hypothesis is that identifying acid and bile stimulated up- or down regulated genes in the normal esophagus and Barrett's epithelium, and characterizing the signaling pathways that are involved, should provide potential diagnostic and therapeutic targets and essential clues regarding the mechanisms of esophageal metaplasia and abnormal cell proliferation in BE.
Our specific aims and hypotheses are: (i) Use a human microarray approach, ex vivo, to identify the genes that are modified in response to acid or bile in normal esophagus, BE and duodenum.
This aim i s based on the hypothesis that the DGE refluxate modulates the genetic program of normal esophageal, BE and duodenal epithelia differently, in a refluxate constituent-dependent fashion. (ii) Identify the acid or bile-induced modified genes in squamous esophageal and Barrett's cell lines.
This aim i s based on the hypothesis that tissue cultured cell lines, due to their ability to provide an unlimited supply of RNA for gene profile analysis, may provide complimentary information to that obtained using ex vivo biopsies. (iii) Study the signaling cascades of protein kinase C, Cox-2, and Src kinase that are involved in acid/bile-induced stimulation, and define their potential interactions.
This aim i s based on the hypothesis that characterizing the signaling pathways that are involved in acid and bile stimulated cell proliferation complements the microarray gene profiling strategies and may provide potential complimentary targets for decreasing the risk of dysplasia and adenocarcinoma in BE. Overall, our study seeks to define the molecular signals that play a role in developing metaplasia and that regulate the acid- and bile-mediated responses in the esophagus.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK063624-05
Application #
7114259
Study Section
Special Emphasis Panel (ZRG1-GMA-2 (01))
Program Officer
Hamilton, Frank A
Project Start
2002-09-30
Project End
2008-06-05
Budget Start
2006-09-01
Budget End
2008-06-05
Support Year
5
Fiscal Year
2006
Total Cost
$390,600
Indirect Cost
Name
Stanford University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
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