Barrett's esophagus (BE), a specialized columnar epithelium, progresses to esophageal adenocarcinoma (EAC) at a rate of ~0.5%/yr. One strategy to prevent cancer is endoscopic ablation. With acid suppression by proton pump inhibitors (PPIs), ablation results in the replacement of BE by (neo)squamous epithelium (NSE). For this approach to be successful, the NSE must be a durable, effective barrier to recurrent injury from reflux. The durability of NSE is uncertain. Ablation by argon plasma coagulation lacks durability,with re-emergence of BE in up to 66% pts. Additionally, recent data suggest that 25% of those undergoing radiofrequency ablation (RFA) had recurrent disease at 1 yr. Moreover, we found evidence of a defective barrier in NSE that emerged following RFA. This defect is similar to that observed in native squamous tissue in GERD. Specifically, NSE exhibited dilated intercellular spaces and functionally had low electrical resistance and high (paracellular) permeability to fluorescein. These abnormalities all indicate a defect in the junctional barrier - one that persists for up to 2 yrs after therapy and while on PPIs. Further, we found that NSE had low claudin-4, an abnormality of the tight junction that could account for impairment in barrier function. We have shown in cell culture that treatment with a flavanoid, Quercetin, resulted in both increased claudin-4 expression and improved barrier function. Therefore, we hypothesize that the defective barrier in NSE results from low claudin-4 and that this defect increases permeability to H+ and promotes recurrent reflux damage to NSE. We also hypothesize that upregulation of claudin-4 by Quercetin will improve barrier function and reduce the vulnerability of NSE.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54CA163060-03
Application #
8567052
Study Section
Special Emphasis Panel (ZCA1-SRLB-1)
Project Start
Project End
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
3
Fiscal Year
2013
Total Cost
$71,932
Indirect Cost
$19,583
Name
Case Western Reserve University
Department
Type
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
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