The incidence of esophageal adenocarcinoma (EAC) is rising faster than that of any other cancer, and the 5- year mortality of this cancer type is 86%. The long-term career objective of the candidate is to develop novel cost-effective strategies for preventing mortality from EAC. Any such strategy will depend on identifying patients at risk for EAC. Barrett's esophagus (BE) is the accepted precursor of EAC. The immediate career objective is to develop novel strategies of identifying patients at risk for BE for the purpose of screening. Obesity is a risk factor for BE and EAC. Others have proposed that this effect is mediated by a mechanical effect promoting gastroesophageal reflux disease. We believe it is unlikely that the risk is due solely to such a mechanical effect;instead, we propose that visceral adipocytes secrete cytokines (adipokines) that promote BE and EAC. Adiponectin, an adipokine whose serum levels are inversely correlated with obesity, inhibits inflammation and promotes apoptosis;deficiency is associated with a number of epithelial cancers. The high molecular weight (HMW) form of adiponectin may be the metabolically active form. We hypothesize that adiponectin deficiency (and the HMW isoform in particular) is closely associated with BE, and is associated with progression of BE toward EAC. We propose a prospective case-control study to estimate the relation between adiponectin in plasma and BE, controlling for potential confounding factors. In addition to examining a potential mechanism to explain the effect of obesity on BE, we hope to identify in adiponectin deficiency a new biomarker of high risk for development of BE. The proposed translational study addresses priorities identified by the National Cancer institute, including to identify """"""""pathophysiologic consequences of reflux, and its interrelationship with BMI, fat distribution, and other factors in the development of esophageal and gastric cardia adenocarcinomas and their precursors."""""""" The candidate's career will be developed through the mentored research experience and through didactic courses in epidemiology and bioinformatics.

Public Health Relevance

The incidence of esophageal adenocarcinoma is rising faster than that of any other cancer in the U.S. This highly fatal cancer is associated with obesity. This study tests the hypothesis that specific substances secreted from fat tissue are strongly associated with the risk of developing esophageal adenocarcinoma. If so, measurement of these substances may be useful in a screening program.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
5K23DK079291-05
Application #
8132798
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Podskalny, Judith M,
Project Start
2007-09-10
Project End
2012-08-31
Budget Start
2011-09-01
Budget End
2012-08-31
Support Year
5
Fiscal Year
2011
Total Cost
$136,155
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Thrift, Aaron P; Anderson, Lesley A; Murray, Liam J et al. (2016) Nonsteroidal Anti-Inflammatory Drug Use is Not Associated With Reduced Risk of Barrett's Esophagus. Am J Gastroenterol 111:1528-1535
Kendall, Bradley J; Rubenstein, Joel H; Cook, Michael B et al. (2016) Inverse Association Between Gluteofemoral Obesity and Risk of Barrett's Esophagus in a Pooled Analysis. Clin Gastroenterol Hepatol 14:1412-1419.e3
Govani, S M; Metko, V; Rubenstein, J H (2015) Prevalence and risk factors for heterotopic gastric mucosa of the upper esophagus among men undergoing routine screening colonoscopy. Dis Esophagus 28:442-7
Rubenstein, Joel H; Morgenstern, Hal; Chey, William D et al. (2014) Protective role of gluteofemoral obesity in erosive oesophagitis and Barrett's oesophagus. Gut 63:230-5
Rubenstein, Joel H; Inadomi, John M; Scheiman, James et al. (2014) Association between Helicobacter pylori and Barrett's esophagus, erosive esophagitis, and gastroesophageal reflux symptoms. Clin Gastroenterol Hepatol 12:239-45
Rubenstein, Joel H; Morgenstern, Hal; Appelman, Henry et al. (2013) Prediction of Barrett's esophagus among men. Am J Gastroenterol 108:353-62
Bedi, Aarti O; Kwon, Richard S; Rubenstein, Joel H et al. (2013) A survey of expert follow-up practices after successful endoscopic eradication therapy for Barrett's esophagus with high-grade dysplasia and intramucosal adenocarcinoma. Gastrointest Endosc 78:696-701
Hur, Chin; Choi, Sung Eun; Rubenstein, Joel H et al. (2012) The cost effectiveness of radiofrequency ablation for Barrett's esophagus. Gastroenterology 143:567-75
Rubenstein, Joel H (2012) Shedding some light on the etiology of adenocarcinomas of the esophagus and gastric cardia. Am J Gastroenterol 107:1814-6
Lewis, Jason J; Rubenstein, Joel H; Singal, Amit G et al. (2011) Factors associated with esophageal stricture formation after endoscopic mucosal resection for neoplastic Barrett's esophagus. Gastrointest Endosc 74:753-60

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