Visualizing oxidative stress using hyperpolarized magnetic resonance

使用超极化磁共振可视化氧化应激

• 批准号: 10162569
• 负责人: Kayvan R Keshari
• 金额: $ 69.38万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 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/10162569
• 关键词: Acute; Address; Aging; Animal Model; Antioxidants; Ascorbic Acid; Biochemical Reaction; Biomedical Engineering; Blood - brain barrier anatomy; Brain; Brain Neoplasms; Cancer Biology; Cell Death; Cells; Cellular Stress; Chemicals; Chemotherapy and/or radiation; Clinical; DNA Damage; Data; Detection; Development; Disease; Dose; Environment; Equilibrium; Face; Feasibility Studies; Foundations; Future; Generations; Glycolysis; Goals; Homeostasis; Human; Image; Imaging technology; In Vitro; Isotopes; Lead; Liquid substance; Magnetic Resonance; Magnetic Resonance Imaging; Malignant Neoplasms; Measurement; Measures; Metabolic; Metabolic Pathway; Metabolism; Methods; Molecular Probes; Monitor; Motivation; Mus; Nerve Degeneration; Neurodegenerative Disorders; Oxidants; Oxidation-Reduction; Oxidative Stress; Oxides; Pathogenesis; Pathology; Patients; Physical Chemistry; Play; Pre-Clinical Model; Process; Pyruvate; Radiation; Radiation therapy; Reactive Oxygen Species; Relaxation; Research; Research Proposals; Role; Signal Transduction; Signaling Molecule; Solid; System; Therapeutic; Time; Tissues; Toxicology; Translating; Translations; Transport Process; Work; ascorbate; brain tumor imaging; cancer therapy; clinical translation; dehydroascorbate; design; docosahexaenoylascorbic acid; experience; first-in-human; human imaging; imaging approach; imaging modality; in vivo; individualized medicine; innovation; metabolic abnormality assessment; metabolic imaging; molecular imaging; mouse model; non-invasive imaging; non-invasive monitor; novel; novel strategies; oxidation; preclinical study; response; small molecule; spectroscopic imaging; standard of care; therapy development; translation to humans; treatment planning; treatment response

PROJECT SUMMARY/ABSTRACT Reactive oxygen species (ROS) are the byproduct of normal metabolism as well as the differential state and environment of the cell. They lead to oxidative stress and can be the causes of multiple pathologies, including cancer. Moreover, oxidative stress and the cell's ability to deal with it can play a major role in the treatment of these diseases. However, current methods to quantify oxidative stress in vivo are severely lacking and to date there is no routine method to non-invasively image redox or oxidative stress in humans. A new platform, hyperpolarized MRI, has the potential to change the way we interrogate metabolism in vivo. We and others have utilized the power of this approach, combined with endogenous substrates, to non-invasively image a metabolic substrate and its subsequent downstream products using conventional MRI. In our preliminary work, we have developed a novel approach to imaging oxidative stress using HP dehydroascorbate (HP DHA), the oxidized form of vitamin C. Using HP DHA, we are able to image the in vivo generation of HP vitamin C and utilize the cells' endogenous system to create a non-invasive redox measurement. Combining this with fast spectroscopic imaging approaches provides a means of readily imaging redox in mice. These exciting developments provide the basis for pursuing the objectives of this innovative proposal to utilize HP DHA MRI to further quantify oxidative stress in vivo. Using HP DHA, we will develop a parameter for conversion to Vitamin C in vivo that quantifies the amount of oxidative stress the cell is under using both acute generation of ROS in the normal brain and models of murine brain tumors treated with radiation. In parallel, we will utilize what we have recently learned about the physical chemistry of hyperpolarized probes to design a more robust and better performing HP DHA. Finally, we will conduct the optimization and toxicology studies necessary to translate HP DHA to humans, aiming to conduct the first-in-human studies of this approach. It is the overarching goal of this proposal to use this novel approach in metabolic imaging and lay the foundation for future metabolic imaging of oxidative stress in patients. This effort will also provide a means of non-invasively monitoring treatment response that aims to increase oxidative stress, which could be readily integrated into standard MRI.

项目摘要/摘要 活性氧（ROS）是正常代谢以及差异状态和 细胞的环境。它们导致氧化应激，可能是多种病理的原因，包括 癌症。此外，氧化应激和细胞应对其处理能力可以在治疗中发挥重要作用 这些疾病。但是，当前量化体内氧化应激的方法严重缺乏，迄今为止 没有常规方法可以非侵入性地图像氧化还原或人类的氧化应激。 一个新的平台超极化MRI具有改变我们在体内询问代谢的方式。我们 其他人则利用了这种方法的力量，结合了内源性底物，非侵入性 使用常规MRI对代谢底物及其随后的下游产物进行图像。在我们的初步中 工作，我们已经开发了一种新型的方法，可以使用HP脱氢抗坏态（HP DHA）对氧化应激进行成像。 维生素C的氧化形式。使用HP DHA，我们能够成像体内生成HP维生素C和 利用细胞的内源系统创建非侵入性氧化还原测量。将其与快速结合 光谱成像方法提供了一种容易在小鼠中成像氧化还原的方法。 这些令人兴奋的发展为追求这一创新提议的目标提供了基础，以利用惠普 DHA MRI在体内进一步量化氧化应激。使用HP DHA，我们将开发一个参数以转换为 维生素C的体内量化细胞正在使用急性生成的氧化应激量 在正常大脑中的ROS和用辐射处理的鼠脑肿瘤模型。同时，我们将利用什么 最近，我们了解了超极化探针的物理化学反应，以设计更健壮的探针 更好地执行HP DHA。最后，我们将进行翻译所需的优化和毒理学研究 HP DHA向人类，旨在对这种方法进行第一个人类研究。 这项提案的总体目标是在代谢成像中使用这种新颖的方法并奠定基础 为了将未来的代谢成像用于患者的氧化应激。这项工作还将提供一种非侵入性的手段 监测旨在增加氧化应激的治疗反应，可以轻易整合到 标准MRI。