Theranostic Metabolic Imaging of Oxidative Stress in Multiple Sclerosis.

多发性硬化症氧化应激的治疗诊断代谢成像。

基本信息

批准号：
10666890
负责人：
Myriam Marianne Chaumeil
金额：
$ 24.23万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-01-23 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10666890
关键词：
Acetates Acetylcysteine Adoption Affect Alzheimer&apos s Disease Amino Acids Antioxidants Ascorbic Acid Autopsy Biological Assay Biopsy Brain Cancer Model Caring Cerebrum Clinical Clinical Management Cysteine Detection Diabetes Mellitus Disease Progression Disease remission Etiology Evaluation Fumarates Glutathione Homeostasis Image Imaging Device Immunohistochemistry Inflammation Inflammatory Injections Injury to Kidney Lead Lesion Light Link Magnetic Resonance Imaging Measures Metabolic Metabolism Methods Monitor Multiple Sclerosis Mus Neurologic Noise Non-Invasive Detection Organ Outcome Oxidation-Reduction Oxidative Stress Oxidative Stress Pathway Pancreas Parkinson Disease Patients Penetration Peripheral Persons Play Population Pre-Clinical Model Process Production Prognostic Marker Quality of life Reaction Reactive Oxygen Species Regimen Relapse Relapsing-Remitting Multiple Sclerosis Reporting Research Resolution Role Scheme Secondary Progressive Multiple Sclerosis Signal Transduction Structure Techniques Testing Therapeutic Tissues Toxic effect Validation alternative treatment clinical practice clinical translation clinically relevant cognitive function data quality detection method effective therapy glucose metabolism imaging approach imaging modality immunomodulatory therapies improved in vivo in vivo imaging innovation magnetic resonance spectroscopic imaging metabolic imaging multimodality multiple sclerosis patient nervous system disorder novel patient population personalized therapeutic precision medicine public health relevance respiratory targeted biomarker targeted treatment theranostics tool translational potential treatment response treatment strategy

项目摘要

ABSTRACT Oxidative stress plays a crucial role in Multiple Sclerosis (MS). Importantly, oxidative stress is more prominent in primary and secondary progressive MS (PP/SPMS) than in the relapsing remitting (RRMS) form, and alternative treatment strategies targeting oxidative stress are being tested for PP/SPMS. Unfortunately, there are presently limited in vivo methods for measuring oxidative stress. Hyperpolarized 13C Magnetic Resonance Spectroscopic Imaging (HP 13C MRSI) is a safe method that detects metabolic reactions in vivo post injection of HP probes. HP [1-13C]-dehydroxyascorbate (DHA) has shown potential for in vivo imaging of oxidative stress in vivo, but causes transient respiratory arrest and pancreatic toxicity, limiting its translational potential. There is thus a need for a new imaging strategy to assess oxidative stress in the brain in vivo. N-acetylcysteine (NAC) is the N-acetyl derivative of the naturally occurring amino acid, L-cysteine, and has been used as an antioxidant in clinical practice for decades. In people living with MS, a recent study reported that NAC significantly increased cerebral glucose metabolism and cognitive function, identifying NAC as a potential therapy. Based on all these findings, we propose to: Aim 1: Optimize and validate HP [1,4-13C]NAC as a theranostic probe to non-invasively detect cerebral redox status in MS mice at clinical field strength: The concentration of [1,4-13C]NAC and the MRSI acquisition scheme will be optimized for detection of the metabolism of [1,4-13C]NAC in the brain of MS mice, to provide the best data quality. Correlations between ex vivo oxidative stress markers and in vivo HP Ac/Cys-to-NAC will be performed to biologically validate our imaging method. Completion of this aim will provide an optimized tool for quantifying in vivo redox state in the MS mouse brain. Aim 2. Apply theranostic metabolic imaging of oxidative stress to monitor response to therapies: We will apply a multimodal metabolic imaging approach combining both HP [1,4-13C]NAC and HP [1-13C]DHA strategies, as well as complementary biological assays, to investigate the effects of a clinically-relevant therapy dimethylfumarate (DMF), a novel potential therapeutic molecule affecting oxidative stress (Acivicin) as well as the effect of NAC itself used as treatment, in a preclinical model of MS. Correlations between ex vivo oxidative stress markers and in vivo HP ratios will be performed to biologically validate our imaging approaches, and compare HP [1,4-13C]NAC and HP [1-13C]DHA strategies. Completion of this aim will validate a new metabolic imaging tool for monitoring therapeutic response linked to changes in oxidative stress in MS in vivo. Overall Impact: The expected overall impact is that, through validation of a new theranostic MR imaging approach allowing for assessment of oxidative stress, and upon clinical translation, results from this project will likely improve the clinical management for MS patients – especially for the SPMS/PPMS population in high need of improved care -, help refine therapy regimens and, ultimately lead to better outcome and patient quality of life.

抽象的氧化应激在多发性硬化症 (MS) 中起着至关重要的作用，重要的是，氧化应激更为突出。原发性和继发性进行性多发性硬化症 (PP/SPMS) 的发生率高于复发缓解型 (RRMS) 型，并且不幸的是，针对氧化应激的替代治疗策略正在测试中。目前用于测量氧化应激的体内方法有限。光谱成像 (HP 13C MRSI) 是一种安全的方法，可检测注射后体内代谢反应 HP 探针。HP [1-13C]-脱羟基抗坏血酸 (DHA) 已显示出在体内氧化应激成像方面的潜力。体内，但会引起短暂的呼吸停止和胰腺毒性，限制了其转化潜力。因此，需要一种新的成像策略来评估体内大脑的氧化应激。 N-乙酰半胱氨酸（NAC）是天然存在的氨基酸L-半胱氨酸的N-乙酰衍生物，具有最近的一项研究报告称，几十年来，它一直被用作多发性硬化症患者的抗氧化剂。 NAC 显着增加脑葡萄糖代谢和认知功能，将 NAC 确定为基于所有这些发现，我们建议：目标 1：优化并验证 HP [1,4-13C]NAC 作为无创检测脑部的治疗诊断探针 MS 小鼠在临床场强下的氧化还原状态：[1,4-13C]NAC 浓度和 MMSI 采集将优化方案以检测 MS 小鼠大脑中 [1,4-13C]NAC 的代谢，以提供离体氧化应激标记物与体内 HP Ac/Cys-to-NAC 之间的相关性将是最佳的。进行生物学验证我们的成像方法，完成这一目标将为我们提供一个优化的工具。量化 MS 小鼠大脑中的体内氧化还原状态。目标 2. 应用氧化应激的治疗诊断代谢成像来监测对治疗的反应：我们将应用结合 HP [1,4-13C]NAC 和 HP [1-13C]DHA 的多模式代谢成像方法策略以及补充生物测定，以研究临床相关疗法的效果富马酸二甲酯（DMF），一种影响氧化应激（Acivicin）的新型潜在治疗分子在 MS 临床前模型中，NAC 本身作为治疗的效果与离体氧化之间的相关性。将进行应激标记和体内 HP 比率以从生物学角度验证我们的成像方法，以及比较 HP [1,4-13C]NAC 和 HP [1-13C]DHA 策略完成此目标将验证新的代谢策略。用于监测与多发性硬化症体内氧化应激变化相关的治疗反应的成像工具。总体影响：预期的总体影响是，通过验证新的治疗诊断 MR 成像允许评估氧化应激的方法，并且在临床转化后，该项目的结果将可能改善多发性硬化症患者的临床管理——尤其是高需求的 SPMS/PPMS 人群改善护理 - 帮助完善治疗方案，最终带来更好的结果和患者的生活质量。