Our major translational goal is to develop a chemopreventive strategy for inhibiting progression of Barrett's esophagus to esophageal adenocarcinoma. We hypothesize that the deleterious effects of hydrophobic bile acids and low pH may be inhibited by the cytoprotective bile acid, ursodeoxycholic acid (UDCA), that was shown to protect cells against oxidative injury. The central hypothesis to be tested in this proposal is that bile acids in combination with low pH induce oxidative stress that leads to DMA damage, genomic instability and apoptosis resistance in Barrett's esophagus. Therefore, an alteration of bile acid composition by ursodeoxycholic acid treatment may be beneficial to Barrett's esophagus patients in the prevention of neoplastic progression.
Three specific aims are proposed to test this hypothesis. First, we will evaluate the effect of a bile acid cocktail and/or low pH on the generation of reactive oxygen species (ROS), oxidative, DNA damage, expression of DNA repair proteins, anti-oxidant and anti-apoptotic proteins in vitro in esophageal cell lines and ex vivo, in BE biopsies. We will determine the effect of acute, repeated and chronic exposure to bile acids and/or low pH (1) on the induction of superoxide, (2) formation of 8-OH-dG, a marker of oxidative DNA damage, (3) expression of DNA repair proteins (i.e. Mlh1, Pms2 and PARP), anti-oxidant (i.e. superoxide dismutases and catalase) and anti-apoptotic proteins (i.e. Mcl-1, survivin, Bcl-xL). Furthermore, we plan to identify patterns of DNA alterations using microarray-based comparative genomic hybridization (CGH) in novel esophageal cell lines developed for resistance to bile acids and/or low pH.
In specific aim #2 we plan to evaluate the effects of UDCA and its conjugated forms [(tauro-ursodeoxycholic acid (TUDCA), glyco- ursodeoxycholic acid (GUDCA)] on ROS production, oxidative DNA damage, genomic instability and the expression of DNA repair proteins, anti-oxidant and anti-apoptotic proteins induced by low pH and cytotoxic bile acids in vitro. Since UDCA is an excellent scavenger of ROS we anticipate that UDCA will reduce damage caused by bile acids and low pH. Finally, in specific aim #3 we propose to conduct a pilot clinical trial to evaluate UDCA as a potential preventive agent that changes the composition of bile acids in the refluxate so that less toxic bile acids are refluxed to the esophagus. Thus, bile acid composition at the baseline and post UDCA treatment will be determined. Furthermore, markers of oxidative stress (8-OH-dG) and proliferation (Ki-67) will be assessed in BE biopsies at the baseline, 6 months on UDCA and 6 months after discontinuation of UDCA using immunohistochemistry in conjunction with image analysis. Our long-term goal is to evaluate factors and molecular mechanisms leading to BE development and/or progression to esophageal adenocarcinoma and to inhibit these processes.
|Daryaei, Iman; Randtke, Edward A; Pagel, Mark D (2017) A biomarker-responsive T2ex MRI contrast agent. Magn Reson Med 77:1665-1670|
|Shkreta, Lulzim; Blanchette, Marco; Toutant, Johanne et al. (2017) Modulation of the splicing regulatory function of SRSF10 by a novel compound that impairs HIV-1 replication. Nucleic Acids Res 45:4051-4067|
|Hingorani, Dina V; Montano, Luis A; Randtke, Edward A et al. (2016) A single diamagnetic catalyCEST MRI contrast agent that detects cathepsin B enzyme activity by using a ratio of two CEST signals. Contrast Media Mol Imaging 11:130-8|
|Liu, Lin; Messer, Karen; Baron, John A et al. (2016) A prognostic model for advanced colorectal neoplasia recurrence. Cancer Causes Control 27:1175-85|
|Chang, Hae Ryung; Nam, Seungyoon; Kook, Myeong-Cherl et al. (2016) HNF4? is a therapeutic target that links AMPK to WNT signalling in early-stage gastric cancer. Gut 65:19-32|
|Harpel, Kaitlin; Leung, Sarah; Rice, Photini Faith et al. (2016) Imaging colon cancer development in mice: IL-6 deficiency prevents adenoma in azoxymethane-treated Smad3 knockouts. Phys Med Biol 61:N60-9|
|Kobes, Joseph E; Daryaei, Iman; Howison, Christine M et al. (2016) Improved Treatment of Pancreatic Cancer With Drug Delivery Nanoparticles Loaded With a Novel AKT/PDK1 Inhibitor. Pancreas 45:1158-66|
|Kurzius-Spencer, Margaret; Harris, Robin B; Hartz, Vern et al. (2016) Relation of dietary inorganic arsenic to serum matrix metalloproteinase-9 (MMP-9) at different threshold concentrations of tap water arsenic. J Expo Sci Environ Epidemiol 26:445-51|
|Tsikitis, Vassiliki L; Potter, Amiee; Mori, Motomi et al. (2016) MicroRNA Signatures of Colonic Polyps on Screening and Histology. Cancer Prev Res (Phila) 9:942-949|
|Fernández-Cuervo, Gabriela; Sinharay, Sanhita; Pagel, Mark D (2016) A CatalyCEST MRI Contrast Agent that Can Simultaneously Detect Two Enzyme Activities. Chembiochem 17:383-7|
Showing the most recent 10 out of 232 publications