Pathology Graduate Training Program
Cellular and Molecular Pathology (CMP) -
Alumni

Name: Michael D. Thompson
Email: Thompson.michael@medstudent.pitt.edu
Lab Phone: 412-648-8146
Mentor Name: Dr. Satdarshan P.S. Monga

Education:
Name of school attended:Washington University in St. Louis
Undergraduate degree: B.A. Biology

Thesis Title/Research Topic:

Identification and understanding of key molecular pathways during normal liver growth and regeneration will be crucial for successful hepatic tissue engineering. Further, it will be crucial to examine such molecular pathways in dysregulated liver growth as seen in hepatic cancer. Our lab has identified -catenin as one such player in liver biology. A central component of the Wnt signaling pathway, -catenin has been shown to be critical in normal growth and development, as well as regulating vital cellular events such as proliferation, apoptosis, and directing cell fate during embryogenesis. Wnt signaling at its receptor frizzled causes an increase in free cytoplasmic -catenin levels, resulting in translocation of -catenin to the nucleus where it binds to an HMG box containing DNA-binding protein T cell factor/lymphoid-enhancing factor (TCF/LEF) family member and controls transcription of various target genes important in proliferation and differentiation. We have found that -catenin is temporally regulated during embryonic liver development, and a significant correlation exists between nuclear and cytoplasmic -catenin and cell proliferation in developing liver. Interestingly, aberrant activation of this pathway has been shown to be a common occurrence in hepatocellular carcinoma. One mutation commonly observed occurs at serine 45, which was previously shown to be important as a phosphorylation site in priming -catenin for subsequent degradation. We have developed a cell line and mouse model that overexpress a serine 45 mutated -catenin which contains an amino acid change to aspartic acid. Thus, -catenin in this model is resistant to degradation allowing for increased activation of its signaling pathway. Our first aim will be to examine the role of -catenin in growth factor induced cell growth and proliferation via in vitro studies with our mutant -catenin cell line. Our second aim will examine activation of this pathway during liver regeneration utilizing a two-thirds partial hepatectomy model, as well as the role of this mutant in dysregulated growth during induction of hepatocarinogenesis. Our final aim will examine the effect of inhibition of this signaling pathway through the use of two compounds, R-Etodolac and pegylated Interferon, which have previously shown to have anti--catenin activity. Ultimately, we hypothesize that increased expression and stabilization of -catenin will lead to an amplified regenerative response and dysregulated liver growth which could provide important insights on this signaling pathway and its implications in hepatic tissue engineering.

Publications:

Powell, T.M., Paul J.D., Hill, J.M., Thompson, M., Benjamin, M., Rodrigo, M., McCoy, J.P., Read, E.J., Khuu, H.M., Leitman, S.F., Finkel, T., and Cannon, R.O, III. Granulocyte Colony-Stimulating Factor Mobilizes Functional Endothelial Progenitor Cells in Patients with Coronary Artery Disease. Arteriosclerosis, Thrombosis, and Vascular Biology 25(2): 196-301. (2005)

Paul, J.D., Powell, T.M., Thompson, M., Benjamin, M., Rodrigo, M., Carlow, A., Annavajjhala, V., Shiva, S., Dejam, A., Gladwin, M.T., McCoy, J.P., Zalos, G., Press, B., Murphy, M., Hill, J.M., Csako, G., Waclawiw, M.A., Cannon, R.O., III. Endothelial Progenitor Cell Mobilization and Increased Intravascular Nitric Oxide in Patients Undergoing Cardiac Rehabilitation. J Cardiopulm Rehabil 27(2): 65-72. (2007)

Thompson, M.D., Monga, S.P. Wnt/Beta-catenin signaling in liver health and disease. Hepatology 45(5):1298-305. (2007)

Behari, J., Zeng, G., Otruba, W., Thompson, M.D., Muller, P., Micsneyi, A., Sekhon, S., Leoni, L., Monga, S.P. R-Etodolac decreases beta-catenin levels along with survival and proliferation of hepatoma cells. J Hepatol 46(5):849-57. (2007)

Apte, U., Zeng, G., Thompson, M.D., Muller, P., Micsenyi, A., Cieply, B., Kaestner, K., Monga, S.P. Beta-Catenin is critical for early postnatal liver growth. Am J Physiol Gastrointest Liver Physiol 292(6): G1578-85. (2007)

Apte, U.*, Thompson, M.D.*, Cui, S., Liu, B., Cieply, B., Monga, S.P. Wnt/beta-catenin signaling mediates oval cell response in rodents. Hepatology. 45(5):1298-305. (2008)

Abstracts/Presentations

Thompson, M.D., Zhang, Y., Gonzales, E.R., Perez, R.S., Riehl, T.E., Stenson, W.F., Park, T.S., and Gidday, J.M. Temporal and Spatial Expression of Cyclooxygenase-2 (COX-2) In Murine Brain Following Focal Stroke. Experimental Biology 2003. (Poster)

Khakoo, A.Y., Arbab, A.S., Lizak, M., Sorger, J., Thompson, M., Read, E., Frank, J.A., and Finkel, T. Iron Labeling of CD133+ Hematopoietic Stem Cells For Intracardiac Visualization by Magnetic Resonance Imaging. Keystone Symposia 2004 Stem Cells (B2) (Poster).

Thompson, M., Payne, T.R., Oshima, H., Okada, M., Kekre, N., Huard, J. Evaluation of injectible SIS scaffold as a cell delivery medium for cardiac cell therapy. Midwest Tissue Engineering Consortium 2005. (Poster)

Rodrigo, M.E., Benjamin, M., Carlow, A., Annavajjhala, V., Dejam, A., Paul, J.D., Powell, T.M., Thompson, M., McCoy, J.P., Zalos, G., Murphy, M., Hill, J.M., Gladwin, M., Orlic, D., Cannon, R.O., III. Contribution of Nitric Oxide to Endothelial Progenitor Cell Mobilization, Survival and Differentiation Potential in Patients with Coronary Artery Disease Undergoing Cardiac Rehabilitation. AHA Scientific Sessions 2005.

Thompson, M., Rodrigo, M.E., Benjamin, M., Carlow, A., Powell, T.M., Paul, J.D., McCoy, J.P., Zalos, G., Hill, J.M., Orlic, D., Cannon, R.O., III. Endothelial Progenitor Cell Mobilization During Cardiac Rehabilitation: Need for Continued Exercise after Completion of Program. AHA Scientific Sessions 2005. (Oral Presentation)

Thompson, M., Apte, U.M., Muller, P., Cieply, B., Monga, S.P.S. Wnt/Beta-Catenin pathway activation during normal postnatal liver growth and development. FASEB Summer Research Conferences 2006: Liver Biology, Development, and Disease. (Poster)

Thompson, M.D., Zeng, G., Cieply, B., Micsenyi, A., Monga, S.P.S. Pegged for destruction: -catenin as a novel target of pegylated interferon. Experimental Biology 2007. (Oral Presentation)

Thompson, M.D., Zeng, G., Cieply, B., Monga, S.P.S. Pegylated Interferon suppresses Wnt/-catenin signaling in serine-45 mutated -catenin liver. MD/PhD National Conference 2007. (Oral Presentation)

Thompson, M.D., Cieply, B., Singh, S., Monga, S.P.S. Regulation of Ser-45 mutated -catenin in transgenic mouse livers. Experimental Biology 2008 (Oral Presentation)

Thompson, M.D., Monga, S.P.S. Pegylated Interferon 2 (Peg-IFN) suppresses -catenin signaling in liver. Experimental Biology 2008 (Oral Presentation)

Thompson, M.D., Cieply, B., Singh, S., Monga, S.P.S. -catenin regulates proliferation and differentiation of oval cells in mouse liver. Experimental Biology 2008 (Poster)

Awards:

CATER Fellowship, Paul L. McLain Award, 2008 ASIP Experimental Pathologist in Graduate Training Merit Award

Ruth L. Kirschstein National Research Service Award, F30, 2008