Barrett's Esophagus, Gastroesophageal Reflux Disease
Conditions
Keywords
Barrett's esophagus, Gastroesophageal Reflux Disease
Brief summary
The purpose of this study is to elucidate mechanisms whereby oxidative stress induced by acute reflux esophagitis: 1) activates p38 to regulate proteins that control the G1/S cell cycle checkpoint, and 2) activates HIFs (hypoxia inducible factors) to cause autocrine VEGF (vascular endothelial growth factor) signaling that triggers the EMT (epithelial-mesenchymal-transition) program in Barrett's esophagus.
Detailed description
Gastroesophageal reflux disease (GERD) and its complication, Barrett's esophagus (BE), are risk factors for esophageal adenocarcinoma. In BE, GERD causes inflammation with oxidative DNA damage and genomic instability that contributes to carcinogenesis. In BE, one response to oxidative stress is p38 pathway activation, which might protect against cancer development by initiating G1 arrest and enabling repair of DNA damage. Inflammation and oxidative stress also might induce epithelial-mesenchymal transition (EMT), the process in which epithelial cells acquire mesenchymal characteristics including the ability to migrate. This study will elucidate mechanisms whereby the oxidative stress of acute reflux esophagitis in BE activates p38 to regulate proteins controlling the G1/S cell cycle checkpoint, and activates HIFs to cause autocrine vascular endothelial growth factor (VEGF) signaling that triggers the EMT program.
Interventions
Acid suppressing medications are stopped for all participants the day after baseline assessment. Subsequent evaluations are performed while the participant is not on acid-suppressing medications. Endoscopy with biopsies will be performed in all patients on day 0, 7, and 14.
Sponsors
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Dallas VA Medical Center
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* U.S. Veteran * Barrett's Esophagus
Exclusion criteria
* Inability to provide informed consent * Pregnancy or breastfeeding * Esophageal varices * Warfarin use * Coagulopathy that precludes safe biopsy of the esophagus * Comorbidity that precludes safe participation in the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in esophageal mucosal inflammation using histopathological assessment from baseline to 14 days | day 0, day 7, and day 14 | Inflammation of the esophageal mucosa will be measured at baseline, 7 days, and at 14 days. Esophageal mucosal inflammation will be measured using esophageal mucosal biopsy specimens, and histopatholgical grading. Mucosal infiltration with inflammatory cells (neutrophils, eosinophils, and lymphocytes) will be measured. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| change in phosoho-p38 from baseline to 14 days | day 0, day 7, and day 14 | phospho-p38 will be measured in the esophageal mucosa at baseline, day 7, and at day 14 |
| Show oxidative DNA damage associated with p38 activation | day 0, day 7, and day 14 | OxiSelect Oxidative DNA Damage ELISA assay of Barrett's mucosa at baseline, day 7, and day 14 |
| change in VEGF from baseline to 14 days | day 0, day 7, and day 14 | VEGF will be measured in the esophageal mucosa at baseline, 7 days, and at day 14 |
| change in APE-1 from baseline to 14 days | day 0, day 7, and day 14 | APE-1 will be measured in the esophageal mucosa at baseline, day 7, and at day 14 |
| change in p38 pathway from baseline to 14 days | day 0, day 7, and day 14 | p38 and components of the p38 pathway will be measured in the esophageal mucosa at baseline, 7 days, and at 14 days |
| change in phospho-NPM1 from baseline to 14 days | day 0, day 7, and day 14 | phospho-NPM1 will be measured in the esophageal mucosa at baseline, day 7, and at day 14 |
| change in miRNA expression from baseline to 14 days | day 0, day 7, and day 14 | miRNAs will be measured in the esophageal mucosa and in exosomes isolated from the blood at baseline, day 7, and day 14 |
| change in HIF expression from baseline to 14 days | day 0, day 7, and day 14 | HIF expression will be measured in the esophageal mucosa at baseline, day 7, and day 14 |
| change in NPM1 from baseline to 14 days | day 0, day 7, and day 14 | NPM-1 will be measured in the esophageal mucosa at baseline, day 7, and at day 14 |
Countries
United States
Outcome results
None listed