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.

项目摘要/摘要 活性氧物种(ROS)是正常代谢的副产品，也是差异状态和 细胞的环境。它们会导致氧化应激，并可能是多种病理的原因，包括 癌症。此外，氧化应激和细胞的处理能力在治疗糖尿病的过程中发挥着重要作用。 这些疾病。然而，目前严重缺乏对体内氧化应激进行量化的方法，而且到目前为止 没有常规的方法来非侵入性地成像人类的氧化还原或氧化应激。 一种新的平台，超极化核磁共振，有可能改变我们在体内询问新陈代谢的方式。我们 还有一些人利用这种方法的力量，结合内源底物，以非侵入性的方式 使用常规核磁共振成像代谢底物及其后续的下游产品。在我们的预赛中 工作中，我们开发了一种使用HP脱氢抗坏血酸(HP DHA)对氧化应激进行成像的新方法， 维生素C的氧化形式使用HP DHA，我们能够成像体内HP维生素C和 利用细胞的内源性系统来创造一种非侵入性的氧化还原测量。将其与FAST结合使用 光谱成像方法提供了一种在小鼠身上容易成像的氧化还原方法。 这些令人振奋的发展为实现这一利用惠普的创新计划的目标奠定了基础 DHA MRI以进一步量化体内的氧化应激。使用HP DHA，我们将开发一个参数以转换为 体内的维生素C，它量化了细胞所处的氧化应激量，使用两种急性生成的 正常大脑和放射治疗的小鼠脑瘤模型中的ROS。同时，我们将利用 我们最近了解了超极化探测器的物理化学，以设计出更强大和 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 惠普DHA给人类，目标是进行这种方法的第一次人体研究。 这项提议的首要目标是将这一新方法应用于代谢成像并奠定基础 用于未来患者氧化应激的代谢成像。这一努力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，这可以很容易地整合到 标准核磁共振。

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