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

基本信息

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
项目类别：
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

项目摘要

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：FLASH 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想不到的新数据有力地支持了以下前提：高剂量率照射，称为 FLASH 放射治疗 (FLASH-RT) 可导致正常细胞显着受损组织，同时保留肿瘤反应，有效地导致治疗窗显着增加以改善放射治疗效果。然而，目前尚不清楚这种效应的机制。项目4 将以令人兴奋的初步数据为基础，卡波金（95% O2；5% CO2）呼吸显着减少了保护正常脑组织，同时增强肿瘤的反应。这个结果以及理论对 O2 在癌症与正常组织中的氧化还原反应差异的考虑提供了推动力研究 O2 的反应作为正常组织和癌组织对 FLASH-RT 差异反应的驱动因素。这些考虑导致了项目 4 的中心假设：有机物的差异代谢 FLASH-RT 后癌症组织与正常组织中的氢过氧化物 (ROOH) 的差异是由不稳定的铁池和脂质过氧化链反应，介导肿瘤与肿瘤的差异反应。正常组织进行 FLASH-RT。这一假设将致力于以下目标：具体目标 1：确定动物呼吸的氧气张力的变化如何改变生物体的结构完整性血管系统、成熟神经元形态、炎症反应的激活以及神经认知效应 FLASH-RT 与传统剂量率暴露对比。具体目标 2：使用 Oxylite 确定 FLASH-RT 后肿瘤组织与正常组织中的 O2 是否发生变化测量结果与动物体内 ROOH 和脂质过氧化下游产物的测量结果相关组织暴露于可观察到正常组织保留的剂量的 FLASH-RT 下。具体目标 3：确定有机氢过氧化物和氧化还原活性金属离子在使用药理学和遗传学方法研究肿瘤与正常组织的敏感性差异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生化机制涉及选择性保留背后的有机氢过氧化物代谢和氧化还原活性铁代谢 FLASH-RT 的正常组织用于脑癌治疗的小鼠模型，并提供了一个新的范例使用 FLASH-RT 来利用癌症与正常细胞代谢的根本差异，以提高治疗效果同时保护正常组织。融入P01：项目4将通过提供基因操纵与P01中的所有项目互动有条件地过表达 GPx 1 和 4 以及铁蛋白的脑癌细胞以及经过验证的生物标志物氧化应激用于测试 FLASH-RT 模型中氧化代谢机制。