Request for Funding

Medical Student Research Fellowship for Summer 2001

Mentor: Rhonda Souza M.D.

Department: Medicine/ Gastroenterology

Room number: VAMC Bldg 43 Room 120

Mail Code: 111B1

Phone number: 214 857-0301

E-mail: rsouza@airmail.net

Project title: Insulin-like Growth Factor II Overexpression in Barrett's esophagus

Human subjects IRB approved project number (where applicable): VAMC 99-42

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 combined with basic research

Brief Description of Project: Gastroesophageal reflux disease (GERD) is a risk factor for esophageal adenocarcinoma. Chronic inflammation by GERD can result in the premalignant condition of Barrett's esophagus. Epithelial cells produce insulin-like growth factor II (IGFII), a potent cell mitogen which stimulates growth and induces apoptosis. In a project begun by a student last summer as part of the MSRF, IGFII expression was found to be significantly elevated in Barrett's esophagus compared to normal duodenal control tissues. However, the mechanism for this increase in IGFII expression is not clear. One potential mechanism by which IGFII expression may be increased is loss of imprinting (LOI). Genomic imprinting is defined as an epigenetic change leading to differential expression of the two parental alleles in somatic cells and usually involves allele specific methylation as the method of gene silencing. IGFII is one of many genes in which the maternal allele is silent due to imprinting. LOI occurs when the normally silent allele is activated. Activation of this second allele can lead to an increase in the gene product. LOI of IGFII has been shown to occur in colorectal carcinomas and recent studies in mice suggest that alterations in the level of IGFII may modify the growth of colorectal adenomas, the precursors of colorectal carcinoma. Using a PCR-based method, this project would investigate whether or not there is LOI of IGFII in esophageal biopsy tissues obtained from patients with Barrett's esophagus. In addition, there are concurrent studies in the lab investigating whether elevated expression levels of IGFII contribute to enhanced growth in human Barrett's-associated adenocarcinoma cell lines.

Previous Research Activities or Publications with Medical Students:

1. Lei, J., Zou, T-T, Shi, Y-Q, Zhou, X-L., Smolinski, K.N., Yin, J., Souza, R.F., Appel, R., Wang, S., Cymes, K., Chan, O., Abraham, J.M., Harpaz, N., and Meltzer, S.M. Infrequent DPC4 gene mutation in esophageal cancer, gastric cancer and ulcerative colitis-associated neoplasms. Oncogene, 13: 2459-2462, 1996.

2. Souza, R.F., Appel, R., Yin, J., Wang, S., Smolinski, K.N., Abraham, J.M., Zou, T-T., Shi, Y-Q., Lei, J., Cottrell, J., Cymes, K., Biden, K., Simms, L., Leggett, B., Lynch, P.M., Frazier, M., Powell, S.M., Harpaz, N., Sugimura, H., Young, J., and Meltzer, S.J. Microsatellite instability in the insulin-like growth factor II receptor gene in gastrointestinal tumors. Nature Genetics, 14: 255-257, 1996.

3. Souza, R.F., Lei, J., Yin, J., Appel, R., Zou, T-T., Zhou, X-L., Wang, S., Rhyu, M-G., Cymes, K., Chan, O., Park, W-S., Krasna, M.J., Greenwald, B.D., Cottrell, J., Abraham, J.M., Simms, L., Leggett, B., Young, J., Harpaz, N., and Meltzer, S.J. A Transforming Growth Factor $1 Receptor Type II Mutation in Ulcerative Colitis-Associated Neoplasms. Gastroenterology, 112: 40-45, 1997.

4. Wang S, Souza RF, Kong D, Yin J, Smolinski KN, Zou T-T, Frank T,Young J, Flanders K, Sugimura H, Abraham JM, Meltzer SJ. Deficient transforming growth factor-$1 activation and excessive insulin-like growth factor II expression in IGFII receptor-mutant tumors. Cancer Research, 57: 2543-2546, 1997.

5. Souza RF, Yin J, Smolinski KN, Zou T-T, Wang S, Shi Y-Q, Rhyu M-G, Cottrell J, Abraham JM, Biden K, Simms L, Leggett B, Powell SM, Sugimura H, Young J, Harpaz N, Shimizu K, Matsubara N, Meltzer SJ. Frequent mutation of the E2F-4 cell cycle gene in primary human gastrointestinal tumors. Cancer Research, 57: 2350-2353, 1997.

6. Souza RF, Wang S, Thakar M, Smolinski KN, Yin J, Zou T-T, Kong D, Abraham JN, Toretsky JA, Meltzer SJ. Expression of the wild-type insulin-like growth factor II receptor gene suppresses growth and causes death in colorectal carcinoma cells. Oncogene, 18: 4063-4068, 1999.

7. Brown G, Stark L, Terada L, Spechler SJ, and Souza RF. Insulin-like Growth Factor II Overexpression in Barrett's Esophagus. Poster presentation, 39th Medical Student Research Forum, UT-Southwestern Medical School, Dallas, TX, January 2001

Return to UT Southwestern Homepage

Return to Student Research Projects Index