The overall objective of the proposed research program is to delineate the interactions between the heat shock response and the effects of ionizing radiation on cells that lead to alterations in radiation resistance and potentially can be exploited therapeutically. The hypothesis to be tested is that specific thermal stress-induced alterations (i.e., damage) inhibit or alter the cells' response to ionizing radiation leading to increased radiation lethality. Thus, the goal of the Program Project is to delineate the interactions between heat and ionizing radiation at the cellular level and to develop radiosensitizers that enhance the radiosensitization by heat shock by the following project goals: 1. Heat-shock induced changes in protein associations with DNA nuclear matrix anchoring regions and DNA repair complexes will be investigated in Project 1 to determine their role in the radiosensitization induced by hyperthermia. This work will also determine if there is sufficient radiosensitization by moderate hyperthermia at the cellular level to have a potential impact on conventional fractionated radiotherapy. 2. The mechanism by which cells become resistant to heat-induced radiosensitization will be addressed in Projects 1 and 3. This project will investigate the accessibility to DNA damaged sites at the nuclear matrix DNA attachment regions and the modulation of the activation of gammaH2AX as potential heat effects that enhance radiosensitization beyond that obtained by moderate hyperthermia alone. 3. The possibility that ATM function and telomere metabolism are involved in the mechanisms that cause radiosensitization and thereby providing an approach for heat-induced radiosensitization to have an increased therapeutic gain will be investigated in Project 2. 4. New gene transcription is a critical step in the heat shock response. The increase in levels of the heat shock proteins is essential to development of resistance to subsequent heat shock. Project 3 will determine the feasibility of using peptide nucleic acid constructs as a method to inhibit the expression of heat shock proteins and enhance heat-induced radiosensitization. 5. The development of chemical radiosensitizers that enhance the radiosensitization induced by hyperthermia will be pursued in Project 4. As a first step, Project 4 will collaborate with Projects 1 and 2 to determine the roles of protein aggregation and inhibition of the ATM and NF-kappaB/p38 signal transduction pathways in radiosensitization by indol based compounds such as indomethacin. This project will then modify indoles to reduce toxicity while enhancing the radiosensitized effects.
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