The overall object of the proposed research program is to test the hypothesis that the cellular and nuclear components involved in various stress responses will be determinants of the response(s) of mammalian cells to therapeutic uses of ionizing radiation. A sufficient condition of this hypothesis is that stress responses involve one or more measurable determinants of the sensitivity to ionizing radiation. Further, such measurable determinants could be candidates for potential clinically relevant predictive assays for possible use in clinical Radiation Oncology. Therefore, we are proposing a series of research projects to investigate the relationships between specific stress response components and radiosensitivity. These stresses include both heat shock and oxidative stress. The projects specifically address these stresses, but also include studies of cell-cycle perturbation, a consequence of stress known to affect radiosensitivity, nuclear determinants of radiosensitivity, and the effects of radiation-induced DNA damage on transcription, a first step in all stress responses. Five individual projects are proposed. Central to the basic theme, two projects, (numbers 3 and 4), will study heat-induced radiosensitization. One of these will emphasize the role of oxidative stress components, the other will study the role of heat-shock proteins. One project, (number 5), will study the mechanisms of recovery from cell-cycle perturbation. The remaining projects, (numbers 1 and 2), will study, respectively the molecular consequences of DNA damage on transcription and the relationship between nuclear matrix mediated DNA organization and radiosensitivity.
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