One of the consequences of the high Socio-economical standards is the increase of diseases related to abdominal obesity, such as gastro-esophageal reflux disease. Barrett’s esophagus is a mucosal adaptation to chronic reflux disease, which is associated with an increased risk of developing esophageal adenocarcinoma. This cancer has become a significant health burden. One effective strategy to control further increase of this highly malignant cancer would be by population wide eradication of Barrett’s esophagus. Hereto, it will be necessary to target the key biological mechanisms that are involved in the process of Barrett’s metaplasia. By means of my recent discovery that Barrett’s esophagus develops through a collaboration of two factors: the caudal homeobox gene CDX-2 and the BMP4/pSMAD pathway, this strategy has become within reach! The objectives are to generate molecular inhibitors and a strategic Barrett model in order to develop and test a molecular cure for Barrett’s esophagus. The key question that will be addressed is: Will inhibition of the BMP4/pSMAD/CDX-2 axis abrogate the homeostasis of intestinal metaplasia and lead to the resolution of Barrett’s esophagus? To answer this question, I propose to synthesize highly specific single domain-antibodies to inhibit the BMP4/pSMAD/CDX-2 axis. With my recent novel insights, I will develop a strategic transgenic Barrett mouse model. I will use a smart drug delivery formula for safe application of these inhibitors in vivo. Finally, the strategic Barrett model will be used to evaluate the novel inhibitors for their efficacy for reversing Barrett’s esophagus back into squamous epithelium. I expect that by the end of the study the stage will be set for future evaluation of these inhibitors in clinical trials for their efficacy to cure Barrett’s esophagus patients. This may lead to population wide control of Barrett’s esophagus, eventually resulting in prevention of further increase of the esophageal adenocarcinoma.