Medical Student Research Fellowship for Summer 2007
Mentor: Rhonda F. Souza MD
Department: Medicine-Division of Liver and Digestive Diseases
Room number: VAMC Blg 43, Room 120
Mail Code: VAMC 111B1
Phone number: 214 857-0301
E-mail: rhonda.souza@verizon.net
Project title: Differences in Cdx-2 expression by acid and bile acids between
esophageal squamous cells from GERD patients with and without Barrett's esophagus.
Human subjects IRB approved project number (where applicable): N/A
Animal subjects IRB approved project number (where applicable): N/A
Project Type (patient-based research, animal-based research, or basic research; this characterization is only to permit a general classification for grouping similar types of projects)
Patient-based basic research (translational)
Brief Description of Project:
Gastroesophageal reflux disease (GERD) has been established as a strong risk
factor for adenocarcinoma of the esophagus, and up to 40% of adult Americans
have GERD. GERD often results in inflammation in the esophageal squamous epithelium
(reflux esophagitis), which, in most individuals, heals through the process
of squamous cell regeneration. In some individuals, however, the reflux-damaged
squamous epithelium heals through a metaplastic process in which squamous cells
are replaced by intestinal-type columnar cells. This condition, called Barrett's
esophagus, predisposes to esophageal adenocarcinoma, a deadly tumor whose incidence
has increased profoundly in the United States over the past several decades.
It is not known why only a minority of individuals with GERD develop Barrett's
esophagus. Recent reports suggest that differences in the molecular mechanisms
triggered when esophageal squamous cells are exposed to refluxed gastric material
might play a role in determining whether reflux esophagitis heals through metaplasia
or through squamous cell regeneration. My research project is to explore the
effects of acid and/or bile acid exposure, the main components of gastric refluxate,
on the induction of the transcription factor Cdx-2. Cdx-2 is a homeobox gene
that encodes a transcription factor that determines an intestinal-type (rather
than a squamous type) of cell development. Data have found that this transcription
factor is increased in esophageal squamous epithelium from patients with Barrett's
esophagus, suggesting that increased expression of the transcription factor
by esophageal squamous cells may lead to the formation of Barrett's esophagus,
an intestinal-type of metaplasia. Using novel, telomerase-immortalized esophageal
squamous epithelial cell lines, developed in our lab, from GERD patients with
and without Barrett's esophagus, we have found differences in the induction
of Cdx-2 mRNA in response to acid and/or bile acid exposure between these esophageal
squamous cell lines. My project will focus on investigating further the mechanism
for the differences in Cdx-2 mRNA expression between the cell lines. Data suggest
that acid and bile acids can demethylate the Cdx-2 promoter as one mechanism
for increased expression. Therefore, I will next determine whether acid alone
or in combination with bile acids increased Cdx-2 expression via promoter demethylation
in the squamous cells lines from Barrett's patients. To confirm Cdx-2 mRNA induction
by acid and acid in combination with bile acids, we have also obtained a Cdx-2
promoter construct attached to luciferase. I will use this construct to determine
whether acid alone or in combination with bile acids increases activity of the
Cdx-2 promoter in the squamous cell lines from GERD patients with and without
Barrett's esophagus. To accomplish these goals, I will work closely with my
mentors Dr. Souza and Dr Xiaofang (Alice) Huo during the tenure of my summer
research fellowship.
Previous Research Activities or Publications with Medical Students:
Previous Research Activities with High School, Undergraduate, and Medical Students:
High School Students
American Gastroenterological Association Student Research Fellowship
Summer 2005 Mizael Quinones
Ang Li
Summer 2006 Xi (Lucy) Chen
Summer 2007 Jane Li, 2007 AGA Foundation-Broad Scholar
Undergraduate Students
UTSWMC Summer Medical Student Research Fellowship
May 1999-September 2000 Gavin Brown
American Gastroenterological Association Student Research Fellowship
Summer 2007 Xinyu Wu
Medical Students
UTSWMC Summer Medical Student Research Fellowship
May-August 2001 William Schmalsteig
June-August 2004 Krina Patel
June-August 2005 Susan Barnes
June-August 2005 Eileen Shi
MD with Distinction in Research Program
November 2003-March 2004 Nathan Susnow
Research Elective
September-October 2004 Tojo Thomas
Publications with Medical Students (Medical Student name in Bold):
1. Feagins LA, Susnow N, Pearson S, Owen C, Schmalstieg WF, Terada LS, Spechler
SJ, Ramirez RD, Souza RF. Gain of Allelic Gene Expression for Insulin-like Growth
Factor 2 Occurs Frequently in Barrett's Esophagus. American Journal of Physiology,
290: G871-875, 2006.
2. Feagins LA, Zhang HY, Zhang X, Hormi-Carver K, Thomas T, Terada LS, Spechler SJ, Souza RF. Mechanisms of oxidant production in esophageal squamous cell and Barrett's cell lines. American Journal of Physiology, 294: G411-417, 2008
Publications with High School Students (High School Student Name in Bold):
1. Feagins LA, Zhang H, Hormi-Carver K, Quinones MH, Thomas D, Zhang X, Terada LS, Spechler SJ, Ramirez RD, Souza RF. Acid has anti-proliferative effects in non-neoplastic Barrett's epithelial cells. American Journal of Gastroenterology, 102: 10-20, 2007.
2. Zhang HY, Zhang X, Chen X, Thomas D, Hormi-Carver K, Elder F, Spechler SJ,
Souza RF. Differences in activity and phosphorylation of MAPK enzymes in esophageal
squamous cells of GERD patients with and without Barrett's esophagus. In revision,
American Journal of Physiology, 2008