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| Ashrafi, Kaveh |
| Barber, Diane L |
| Bernstein, Harold S. |
| Black, Brian L |
| Blanc, Paul D |
| Boushey, Homer A |
| Broaddus, V Courtney |
| Brown, James K |
| Caughey, George H |
| Chapman, Harold A |
| Charo, Israel F |
| Chatterjee, Kanu |
| Chuang, Pao-Tien |
| Clyman, Ronald I |
| Conklin, Bruce R |
| Coughlin, Shaun R |
| Derynck, Rik M |
| Dobbs, Leland G |
| Eisner, Mark D |
| Engel, Joanne N |
| Erle, David J |
| Fahy, John Vincent |
| Farese, Robert V |
| Fielding, Christopher J |
| Fielding, Phoebe |
| Fineman, Jeffrey R |
| Glantz, Stanton A |
| Grossman, William |
| Hawgood, Samuel |
| Ingraham, Holly A |
| Jan, Lily Y |
| Kan, Yuet W |
| Kane, John P |
| Kornberg, Thomas B |
| Kurtz, Theodore W |
| Kwok, Pui-Yan |
| Lazarus, Stephen C |
| Malloy, Mary J. |
| Martin, Gail R |
| Matthay, Michael A |
| Mcdonald, Donald M |
| Mikawa, Takashi |
| Minor, Daniel L |
| Mostov, Keith E |
| Nadel, Jay A |
| Ordahl, Charles P |
| Pitas, Robert E |
| Reiter, Jeremy F. |
| Rosen, Steven D |
| Shaw, Robin M. |
| Sheppard, Dean |
| Simpson, Paul C |
| Stainier, Didier Y. R. |
| Wang, Rong |
| Weiner, Orion D |
| Weisgraber, Karl H |
| Weiss, Arthur |
| Weiss, Ethan J |
| Werb, Zena |
| Wiener-Kronish, Jeanine |
| Young, William L |
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CVRI Scientists
V. Courtney Broaddus, M.D.
Professor of Medicine
Research Interests:
Role of apoptosis in asbestos-induced malignancy. Molecular interaction of asbestos fibers with mesothelial cells, specifically with regard to the role of cell surface adhesion receptors.
Summary:
Apoptosis is a highly regulated process of cell death, allowing the deletion of cells that are damaged or otherwise targeted for destruction. Resistance to apoptosis underlies both the development and the survival of tumors. Understanding the sites of resistance in tumors may lead to more effective therapy. Two signaling pathways are known to activate the proteases called caspases that mediate apoptosis: one, the DNA damage pathway which involves a mitochondrial step in order to activate caspases and the other the death ligand pathway which can bypass mitochondria to activate caspases directly. Crosstalk between the pathways may lead to synergistic apoptotic responses.
We study apoptosis in mesothelioma and lung cancer lines, as models for highly resistant solid tumors. A major focus of the laboratory is 1) to identify mechanisms of resistance to apoptosis in these lines and 2) to identify means of amplifying apoptosis. We have now described a synergistic apoptotic response of mesothelioma lines when exposed to both a death ligand, TNF-related apoptosis inducing ligand (TRAIL), and chemotherapeutic agents. The synergy can be shown to involve amplification of mitochondrial depolarization and amplified release of cytochrome c. We are now studying the signaling steps by which these two pathways (death receptor and DNA damage) converge on the mitochondria andamplify apoptotic death. Other synergistic combinations appear to act at different levels within the cell, e.g. by increasing expression of the death receptors. Some examples of interest are the use of TRAIL or fas ligand together with proteasome inhibitors, with NFkappa B inhibition, and with triptolide, an inhibitor of cell arrest. In parallel in vivo studies, we are exploring synergistic effects in a nude mouse model of mesothelioma.
In other work, we are starting microarray analysis of the response of mesothelial cells to toxic entities, such as asbestos fibers. In this approach, now called toxicogenomics, microarray studies of global cell responses to toxic agents may identify patterns of responses associated with toxicity. The analysis can highlight previously unrecognized toxic interactions with cells, allowing new hypotheses to be developed and explored.
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