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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：
10402394
负责人：
Kayvan R Keshari
金额：
$ 65.39万
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/10402394
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 small molecule spectroscopic imaging standard of care therapy development 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.

项目总结/文摘