Visualizing oxidative stress using hyperpolarized magnetic resonance

使用超极化磁共振可视化氧化应激

基本信息

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
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/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

项目摘要

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.

项目概要/摘要活性氧 (ROS) 是正常代谢以及微分状态和代谢的副产品。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，氧化应激和细胞处理氧化应激的能力可以在治疗中发挥重要作用这些疾病。然而，目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对人体氧化还原或氧化应激进行非侵入性成像。超极化 MRI 是一个新平台，有可能改变我们研究体内代谢的方式。我们和其他人利用这种方法的力量，结合内源性底物，以非侵入性方式使用传统 MRI 对代谢底物及其后续下游产物进行成像。在我们的初步在工作中，我们开发了一种使用 HP 脱氢抗坏血酸 (HP DHA) 来成像氧化应激的新方法，维生素 C 的氧化形式。使用 HP DHA，我们能够对 HP 维生素 C 的体内生成进行成像，并利用细胞的内源系统来创建非侵入性氧化还原测量。将此与快速结合起来光谱成像方法提供了一种轻松成像小鼠氧化还原的方法。这些令人兴奋的发展为实现利用惠普这一创新提案的目标奠定了基础 DHA MRI 可进一步量化体内氧化应激。使用 HP DHA，我们将开发一个参数来转换为体内维生素 C 可通过急性生成来量化细胞所承受的氧化应激量正常大脑和经放射治疗的小鼠脑肿瘤模型中的ROS。同时，我们将利用什么我们最近了解了超极化探针的物理化学，以设计更坚固且更可靠的探针。 HP DHA 性能更好。最后，我们将进行翻译所需的优化和毒理学研究 HP DHA 应用于人类，旨在对这种方法进行首次人体研究。该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方法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成像。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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