Radiosensitization by the Cellular Stress Response

描述(由申请人提供)：拟议研究计划的总体目标是描述热休克反应和电离辐射对细胞的影响之间的相互作用，这些影响导致辐射抗性的变化，并有可能被用于治疗。需要检验的假设是，特定的热应激诱导的改变 (即损害)抑制或改变细胞对电离辐射的反应，导致辐射致死性增加。因此，该项目的目标是在细胞水平上描述热和电离辐射之间的相互作用，并通过以下项目目标来开发增强热休克辐射增敏的放射增敏剂：1.项目1将研究热休克诱导的与DNA核基质锚定区域和DNA修复复合体相关的蛋白质的变化，以确定它们在高温诱导的放射增敏中的作用。这项工作还将确定在细胞水平上是否有足够的中等热疗放射增敏作用，从而对常规分割放射治疗产生潜在影响。2.细胞对热诱导放射增敏的抗性机制将在项目1和3中解决。本项目将研究核基质DNA附着区DNA损伤部位的可获得性以及伽马H_2AX激活的调节作为潜在的热效应，这些热效应可增强放射增敏，而不是单纯的中等热疗。3.ATM功能和端粒代谢参与了辐射增敏的机制，从而为热诱导放射增敏提供了一条增加治疗收益的途径。新的基因转录是热休克反应中的关键步骤。热休克蛋白水平的增加对于发展对后续热休克的抵抗力是必不可少的。项目3将确定使用肽核酸结构作为一种方法来抑制热休克蛋白的表达和增强热诱导的放射增敏的可行性。5.加强高温辐射增敏的化学放射增敏剂的开发将在项目4中进行。作为第一步，项目4将与项目1和2合作，以确定蛋白质聚集和抑制ATM和NF-kappaB/p38信号转导通路在吲哚美辛等吲哚类化合物放射增敏中的作用。然后，该项目将对吲哚进行修饰，以降低毒性，同时增强辐射增敏效果。

DESCRIPTION (provided by applicant): 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.