Radiosensitization by the Cellular Stress Response

细胞应激反应的放射增敏

• 批准号: 7258803
• 负责人: JOSEPH L ROTI ROTI
• 金额: $ 168.48万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7258803
• 关键词: Radiosensitization; Cellular; Stress; Response

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.

描述（由申请人提供）： 拟议的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，导致辐射抗性的改变，并可能被利用治疗。 有待检验的假设是，特定的热应力诱导的变化 (i.e.,损伤）抑制或改变细胞对电离辐射的反应，导致辐射致死率增加。 因此，该计划项目的目标是在细胞水平上描述热与电离辐射之间的相互作用，并开发通过热休克增强放射增敏作用的放射增敏剂，其项目目标如下：1.热休克诱导的蛋白质与DNA核基质锚定区和DNA修复复合物的变化将在项目1中进行研究，以确定它们在高温诱导的放射增敏中的作用。 这项工作还将确定是否有足够的放射增敏适度高温在细胞水平上有一个潜在的影响，对传统的分割放疗。 2.细胞对热诱导放射增敏的抵抗机制将在项目1和3中讨论。 该项目将研究在核基质DNA附着区的DNA损伤位点的可及性和γ H2 AX激活的调节，作为潜在的热效应，其增强放射增敏作用超过仅通过中度热疗获得的效果。 3.项目2将研究ATM功能和端粒代谢参与导致放射增敏的机制的可能性，从而为热诱导放射增敏提供一种增加治疗增益的方法。 4.新基因的转录是热休克反应的关键步骤。 热休克蛋白水平的增加对随后的热休克抗性的发展是必不可少的。 项目3将确定使用肽核酸构建体作为抑制热休克蛋白表达和增强热诱导放射增敏的方法的可行性。 5.将在项目4中继续开发化学放射增敏剂，以增强热疗诱导的放射增敏作用。 作为第一步，项目4将与项目1和2合作，确定蛋白质聚集和ATM和NF-κ B/p38信号转导通路抑制在吲哚类化合物（如吲哚美辛）放射增敏中的作用。然后，该项目将修改吲哚以降低毒性，同时增强放射增敏作用。