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: 10612868
• 负责人: Kayvan R Keshari
• 金额: $ 64.67万
• 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/10612868
• 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; Learning; 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; 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; Visualization; Work; ascorbate; blood-brain barrier crossing; 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; small molecule; spectroscopic imaging; standard of care; 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.

项目总结/摘要 活性氧（ROS）是正常代谢的副产物，也是细胞内的差异状态， 细胞的环境。它们会导致氧化应激，并可能导致多种病理，包括 癌此外，氧化应激和细胞处理它的能力可以在治疗中发挥重要作用。 这些疾病。然而，目前的方法来量化体内氧化应激是严重缺乏和日期 没有常规方法对人体的氧化还原或氧化应激进行非侵入性成像。 一个新的平台，超极化MRI，有可能改变我们询问体内代谢的方式。我们 和其他人已经利用这种方法的力量，结合内源性底物， 使用常规MRI对代谢底物及其后续下游产物进行成像。在我们的初步调查中 工作，我们已经开发了一种新的方法来成像氧化应激使用HP脱氢抗坏血酸（HP DHA）， 维生素C的氧化形式。使用HP DHA，我们能够成像HP维生素C和维生素D的体内生成。 利用细胞的内源性系统来创建非侵入性氧化还原测量。结合快速 光谱成像方法提供了一种容易对小鼠中的氧化还原进行成像的方法。 这些令人兴奋的发展为实现这一创新提案的目标提供了基础， DHA MRI进一步量化体内氧化应激。使用HP DHA，我们将开发一个转换参数， 维生素C在体内定量的氧化应激的细胞是在使用两个急性代， 放射治疗的正常脑和小鼠脑肿瘤模型中的ROS。同时，我们将利用 我们最近已经了解了超极化探针的物理化学，以设计更坚固和 更好地执行HP DHA。最后，我们将进行必要的优化和毒理学研究， HP DHA用于人类，旨在进行这种方法的首次人体研究。 这项提案的首要目标是在代谢成像中使用这种新方法， 用于未来患者氧化应激的代谢成像。这项工作还将提供一种非侵入性的手段， 监测治疗反应，旨在增加氧化应激，这可以很容易地整合到 标准MRI。

项目成果

High Fructose Drives the Serine Synthesis Pathway in Acute Myeloid Leukemic Cells.

• DOI: 10.1016/j.cmet.2020.12.005
• 发表时间: 2021-01-05
• 期刊: Cell metabolism
• 影响因子: 29
• 作者: Jeong S;Savino AM;Chirayil R;Barin E;Cheng Y;Park SM;Schurer A;Mullarky E;Cantley LC;Kharas MG;Keshari KR
• 通讯作者: Keshari KR