PROJECT SUMMARY/ABSTRACT Esophageal adenocarcinoma (EA) is a serious clinical problem due to its high and rapidly increasing incidence rate, and the limited treatment options currently available. This disease has now overtaken other histological types of esophageal tumors in the US. The major risk factor for EA is gastroesophageal reflux disease (GERD), which affects 10 to 20% of the US population. Under conditions of GERD, esophageal cells are ex- posed to acidic gastric juice frequently mixed with duodenal bile acids. The reflux exposure causes chronic inflammation, and excessive tissue and DNA damage, resulting in the accumulation of tumorigenic alterations and progression to EA through Barrett's metaplasia (BE). However, the majority of GERD and BE patients re- cover without malignant transformation, with only a fraction going on to develop an esophageal tumor. It is therefore important to uncover mechanisms that underlie tumor progression, to enable both the identification of targets for screening at risk patients and the development of new preventive therapies for esophageal tumors. We have developed an innovative hypothesis to investigate specific mechanisms of DNA damage repair in conditions of esophageal reflux injury and to apply this knowledge to design novel chemopreventive therapies. This hypothesis is supported by strong preliminary data from human tissues, animal models, and extensive in vitro studies. We have demonstrated that the p73 protein plays a critical role in esophageal tumorigenesis and regulation of DNA damage repair under conditions of esophageal reflux injury caused by GERD. We have also identified a new group of chemopreventive compounds that can specifically activate the protective function of p73 and decrease DNA damage caused by reflux. We will build on these findings to further investigate the role played by p73 and other members of the p53 protein family in the progression to esophageal adenocarcinoma. In aim 1, we will dissect the mechanisms of DNA damage repair regulated by p73 under conditions of esophageal reflux. In aim 2, we will investigate esophageal tumorigenesis in vivo. We will employ gastroesophageal reflux injury mouse models and esophageal organotypic cultures to recapitulate human GERD-associated pathology and dissect the mechanisms of DNA damage repair. These studies will be complemented with analyses of human esophageal precancerous and cancerous lesions. In aim 3, we will explore the chemopreventive potential of compounds that induce the p73 protective activity under conditions of GERD. Our findings will have a strong impact on the understanding of multistep tumorigenesis associated with GERD and BE. Importantly, our results could help to reveal potential risk factors for esophageal tumor development and lay the groundwork for development of novel chemopreventive approaches in at risk patients with GERD and BE.