Project 4: Mechanistic Basics of FLASH Effect: Role of O2

项目 4：FLASH 效应的机械基础知识：O2 的作用

• 批准号: 10415036
• 负责人: Charles Limoli
• 金额: $ 40.44万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10415036
• 关键词: Adjuvant; Animal Model; Animals; Biochemical; Biological; Biological Markers; Blood; Brain Neoplasms; Breathing; Cancer Survivor; Carbogen; Carbon Dioxide; Cell Respiration; Cellular Metabolic Process; Clinical; Clinical Trials; Data; Development; Dose; Dose-Rate; Electrons; Exposure to; Ferritin; Free Radicals; Hydrogen Peroxide; Inflammatory Response; Ions; Lead; Lipid Peroxidation; Malignant Neoplasms; Malignant neoplasm of brain; Measurement; Mediating; Metabolism; Metals; Modeling; Morbidity - disease rate; Morphology; Neurocognitive; Neurons; Normal Cell; Normal tissue morphology; Outcome; Oxidation-Reduction; Oxidative Stress; Oxygen; Pharmacology; Photons; Radiation; Radiation Physics; Radiation therapy; Radiochemistry; Reaction; Role; Stress Tests; Testing; Therapeutic; Therapeutic Index; Time; Tissues; Treatment Efficacy; Tumor Tissue; animal tissue; ascorbate; base; brain tissue; cancer cell; cancer therapy; chemoradiation; cost; functional outcomes; genetic approach; genetic manipulation; glutathione peroxidase; improved; innovation; iron metabolism; irradiation; metal chelator; mortality; mouse model; overexpression; preservation; response; tissue injury; tumor

Project Summary/Abstract - Project 4: Mechanistic Basics of FLASH Effect: Role of O2 Recently, exciting and unexpected new data in several animal models strongly supports the premise that ultra- high dose rate irradiation termed FLASH radiotherapy (FLASH-RT) can result in significant sparing of normal tissue while preserving tumor responses, effectively leading to significant increases in the therapeutic window for improving radiotherapy outcomes. However, the mechanisms for this effect are currently unknown. Project 4 will build on the exciting preliminary data that carbogen (95% O2; 5% CO2) breathing significantly diminished the protection of normal brain tissue while enhancing the responses of tumors. This result as well as theoretical considerations of the differential redox reactions of O2 in cancer versus normal tissues provides the impetus to study the reactions of O2 as drivers of the differential responses of normal and cancer tissue to FLASH-RT. These considerations have led to the central hypothesis in Project 4 that differential metabolism of organic hydroperoxides (ROOH) in cancer versus normal tissues following FLASH-RT, caused by differences in labile Fe pools and lipid peroxidation chain reactions, mediates the differential responses of tumor vs. normal tissues to FLASH-RT. This hypothesis will be pursed in the following Aims: Specific Aim 1: Determine how varying the O2 tension that animals breathe alters the structural integrity of the vasculature, mature neuronal morphology, activation of inflammatory responses, and neurocognitive effects of FLASH-RT versus conventional dose rate exposure. Specific Aim 2: Determine if changes in O2 in tumor versus normal tissues following FLASH-RT using Oxylite measurements correlate with measurements of ROOH and downstream products of lipid peroxidation in animal tissues exposed to FLASH-RT at doses where normal tissue sparing is observed. Specific Aim 3: Determine the causal involvement of organic hydroperoxides and redox active metal ions in the differential sensitivity of tumor versus normal tissues using pharmacological and genetic approaches to manipulate glutathione peroxidases (GPx) 1 and 4 as well as metal chelators that inhibit Fe redox cycling. Scientific Impact: The successful completion of this project will clearly define biochemical mechanisms involving organic hydroperoxide metabolism and redox active iron metabolism underlying the selective sparing of normal tissues from FLASH-RT in mouse models of brain cancer therapy as well as providing a new paradigm for using FLASH-RT to exploit fundamental differences in cancer vs. normal cell metabolism for increasing treatment efficacy while protecting normal tissues. Integration into the P01: Project 4 will interact with all projects in the P01 by providing genetically manipulated brain cancer cells that conditionally overexpress GPx 1 and 4 as well as ferritin and validated biomarkers of oxidative stress for testing mechanisms of oxidative metabolism in models of FLASH-RT.

项目摘要/摘要 - 项目4：闪光效应的机械基础知识：O2的作用 最近，几种动物模型中令人兴奋且意外的新数据强烈支持了以下前提。 高剂量率辐照称为闪光放疗（闪存-RT）可能会导致正常的显着保留 组织同时保存肿瘤反应，有效地导致治疗窗口显着增加 用于改善放射疗法的结局。但是，目前尚不清楚这种效果的机制。项目4 将建立在碳原（95％O2; 5％CO2）呼吸显着减少的令人兴奋的初步数据的基础上 保护正常的脑组织，同时增强肿瘤的反应。这个结果以及理论 O2在癌症与正常组织中的差异氧化还原反应的考虑为 研究O2作为正常和癌组织对闪存的差异反应的驱动因素的反应。 这些考虑因素导致了项目4的中心假设，即有机的差异代谢 flash-rt之后的癌症与正常组织的氢过氧化物（ROOH），这是由差异引起的 不稳定的Fe池和脂质过氧化链反应介导了肿瘤VS的差异反应。 正常的组织到闪存。该假设将在以下目的中提出： 特定目的1：确定动物呼吸的O2张力如何改变 脉管系统，成熟的神经元形态，炎症反应的激活以及神经认知作用 Flash-RT与常规剂量率暴露。 特定目标2：确定使用oxylite在Flash-RT之后肿瘤与正常组织中O2的变化是否变化 测量与动物中脂质过氧化的ROOH和下游产物的测量相关 在观察到正常组织较高的剂量下暴露于闪存的组织。 特定目标3：确定有机氢过氧化物和氧化还原活性金属离子的因果关系 使用药理学和遗传学方法的肿瘤与正常组织的差异敏感性 操纵谷胱甘肽过氧化物酶（GPX）1和4以及抑制FE氧化还原循环的金属螯合剂。 科学影响：该项目的成功完成将明确定义生化机制 涉及有机氢过氧代谢和氧化还原活性铁代谢的选择性保留 脑癌疗法小鼠模型中闪存的正常组织以及提供新的范式 使用Flash-RT利用癌症与正常细胞代谢的基本差异以增加 治疗功效，同时保护正常组织。 集成到P01：项目4将通过提供基因操纵来与P01中的所有项目进行交互 有条件过表达GPX 1和4的脑癌细胞以及铁蛋白和验证的生物标志物 闪光灯模型中氧化代谢的测试机制的氧化应激。