Development and Translation of D-glucose as an MRI Contrast Agent for Multiple Sclerosis

D-葡萄糖作为多发性硬化症 MRI 造影剂的开发和转化

• 批准号: 10268261
• 负责人: Xiang Xu
• 金额: $ 24.88万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-30 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10268261
• 关键词: 3-Dimensional; Adverse effects; Affect; Award; Blood - brain barrier anatomy; Brain; Brain region; Cell Nucleus; Chelating Agents; Chemicals; Chronic; Clinic; Clinical; Contrast Media; Data; Deposition; Development; Diagnosis; Disease; Disease Progression; Dose; Enhancing Lesion; Event; Evolution; Fund Raising; Gadolinium; Gliosis; Glucose; Goals; Image; Imaging Techniques; Inflammation; Inflammatory; Infusion procedures; Intravenous; Intravenous infusion procedures; Kidney Diseases; Kidney Failure; Knowledge; Laboratories; Leadership; Lesion; MRI Scans; Magnetic Resonance Imaging; Measures; Mentors; Mentorship; Methods; Mind; Minor; Monitor; Multiple Sclerosis; Multiple Sclerosis Lesions; Mus; Nephrogenic Systemic Fibrosis; Nerve Degeneration; Noise; Pathologic; Pathology; Patients; Pattern; Periodicity; Permeability; Phase; Physiology; Process; Prognosis; Protocols documentation; Protons; Renal function; Reporting; Research; Research Proposals; Resolution; Risk; Scanning; Series; Signal Transduction; Students; Symptoms; T2 weighted imaging; Techniques; Testing; Time; Tissues; Training; Translating; Translations; Treatment Efficacy; Water; base; biomaterial compatibility; blood-brain barrier disruption; career; career development; clinical practice; cohort; contrast enhanced; contrast imaging; cost; follow-up; glucose uptake; gray matter; human subject; imaging agent; magnetic field; multiple sclerosis patient; nervous system disorder; peace; programs; recruit; remyelination; skills; sugar; tissue repair; tumor

Project Summary Multiple sclerosis (MS) is a disabling neurological disorder that is estimated to affect more than 2.3 million people worldwide. Gadolinium (Gd) contrast enhanced MRI is routinely used in the clinics and is the most sensitive test for establishing diagnosis, predicting prognosis and evaluating treatment efficacy of MS disease. While Gd based contrast agents have demonstrated to be very safe, they have the potential for adverse effects in patients with kidney diseases. In addition, it recently has been reported that the Gd agent can be deposited in deep gray matter nuclei after repeated administration to patients with intact renal function. Based on such issues, there is an urgent need to develop safe alternative contrast agents, especially for MS disease since patients are subjected to periodic scans. The overall goal for this research proposal is to develop and translate to the clinic the use of D-glucose as an intravenous MRI contrast agent for imaging blood-brain-barrier (BBB) disruption in MS. In addition, since the size of D-glucose molecules are smaller than Gd agents, they may be more amenable to leak into lesions with minor BBB disruption, hence provide a more sensitive means to detect lesions at an earlier stage. Preliminary data on mice and human subjects show that intravenous infusion of D-glucose provides MRI contrast that distinguishes the tumor and MS lesions from the unaffected brain region using the chemical exchange saturation transfer (CEST) MRI technique. The data shows that the CEST contrast is enhanced upon D-glucose infusion in tumors and some MS lesions where BBB disruption is suspected. To achieve the goal of the proposal, Dr. Xu will develop 3D whole brain, high resolution CEST MRI techniques that are suitable for imaging MS lesions first at 7 Tesla and subsequently translate the technique to 3 Tesla scanners for patient studies. During the R00 phase, the lesion enhancement patterns for both glucose CEST and Gd will be compared in a cohort of MS patients to validate the feasibility of using D-glucose as a contrast agent. The successful completion of this project will: 1) provide a natural and biodegradable MRI contrast agent for imaging MS lesions; 2) provide a 3D whole brain CEST MRI protocol for imaging MS and other neurological disorders; 3) provide a possible means to capture MS lesions at an earlier stage than conventional Gd agents and enhance our understanding of the correlation between MS pathology and clinical MRI findings. The new skills and knowledge that Dr. Xu will develop during the training period of the project will not only be crucial for the successful completion of the project and her immediate scientific goals, they will also become the pillars for the research program she will build in her own independent laboratory. The career development activity and mentorship during the award period will prepare her for the practical aspects of research leadership, mentoring and fund raising, which are critical for her career as an independent research leader.

项目摘要 多发性硬化症（MS）是一种致命的神经系统疾病，估计会影响超过230万人 全世界。 Gadolinium（GD）对比度增强MRI通常在诊所中使用，是最敏感的测试 用于建立诊断，预测预后和评估MS疾病的治疗功效。而GD基于GD 对比剂已经证明非常安全，它们有可能对 肾脏疾病。此外，最近有报道说GD代理可以沉积在深灰色中 重复给具有完整肾功能的患者进行重复给药后的物质核。基于此类问题，有 迫切需要开发安全的替代对比剂，尤其是对于MS疾病，因为患者是 进行定期扫描。该研究建议的总体目标是发展并转化为 诊所将D-葡萄糖用作静脉内MRI对比剂对血脑屏障成像（BBB） MS中断。另外，由于D-葡萄糖分子的大小小于GD剂，因此可能是 更适合泄漏到小BBB中断的病变中，因此提供了一种更敏感的方法来检测 病变在较早的阶段。 关于小鼠和人类受试者的初步数据表明，静脉输注D-葡萄糖可提供MRI 对比，将肿瘤和MS病变与未受影响的大脑区域区分开 交换饱和转移（CEST）MRI技术。数据表明，CEST的对比度增强了 肿瘤中的D-葡萄糖输注和一些怀疑BBB破坏的MS病变。实现目标 该提议将开发3D整个大脑，高分辨率CEST MRI技术，适合 首先将MS病变成像在7 Tesla处，然后将技术转换为3种特斯拉扫描仪的患者 研究。在R00阶段，将比较葡萄糖CEST和GD的病变增强模式 在一组MS患者中，以验证使用D-葡萄糖作为对比剂的可行性。 该项目的成功完成将：1）提供自然且可生物降解的MRI对比剂 用于成像MS病变； 2）提供3D整个大脑CEST MRI方案，用于成像MS和其他神经系统 疾病； 3）提供了一种可能在更早的阶段捕获MS病变的方法 并增强我们对MS病理学与临床MRI发现之间相关性的理解。新的 Xu博士将在项目培训期间发展的技能和知识不仅至关重要 该项目的成功完成及其直接的科学目标，它们也将成为 她将在自己的独立实验室中构建的研究计划。职业发展活动和 奖励期间的指导将使她为研究领导的实际方面和指导做好准备 和筹款，这对于她作为独立研究领袖的职业至关重要。