权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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.

摘要