The mechanisms that mediate cellular sensitivity to apoptotic stimuli are poorly understood. Considerable data suggests that reactive oxygen intermediates (R01s) may play a critical role in this regard. For example, the PI has demonstrated that increases in intracellular 02- appears to protect cells from Fas-mediated death. In this proposal, the PI plans to: 1) use various agents to alter intracellular 02- production in a variety of different cells types stimulated to die so that the generalizability of this observation can determined; 2) examine the effects of redox balance on caspase activity; 3) determine if Bcl-2 alters redox state in cells; 4) evaluate the effects of altered redox state on apoptosis sensitivity of tumor cells in vivo; and 5) determine if activation-associated changes in lymphocyte sensitivity to apoptotic stimuli is redox state dependent.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM054176-03
Application #
6019146
Study Section
Human Embryology and Development Subcommittee 1 (HED)
Program Officer
Anderson, James J
Project Start
1997-08-01
Project End
2001-07-31
Budget Start
1999-08-01
Budget End
2001-07-31
Support Year
3
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02199
Hampton, Mark B; Stamenkovic, Ivan; Winterbourn, Christine C (2002) Interaction with substrate sensitises caspase-3 to inactivation by hydrogen peroxide. FEBS Lett 517:229-32
Yu, Q; Stamenkovic, I (2001) Angiopoietin-2 is implicated in the regulation of tumor angiogenesis. Am J Pathol 158:563-70
Mitsiades, N; Poulaki, V; Tseleni-Balafouta, S et al. (2000) Thyroid carcinoma cells are resistant to FAS-mediated apoptosis but sensitive to tumor necrosis factor-related apoptosis-inducing ligand. Cancer Res 60:4122-9
Yu, Q; Stamenkovic, I (1999) Localization of matrix metalloproteinase 9 to the cell surface provides a mechanism for CD44-mediated tumor invasion. Genes Dev 13:35-48