Real time imaging of immune cells and glutamate dynamics by PET and metabolic MRI

通过 PET 和代谢 MRI 对免疫细胞和谷氨酸动态进行实时成像

• 批准号: 10371637
• 负责人: Caroline Guglielmetti
• 金额: $ 9.39万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-08 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10371637
• 关键词: Amides; Amyotrophic Lateral Sclerosis; Animals; Anti-Inflammatory Agents; Astrocytes; Biochemical Reaction; Blood - brain barrier anatomy; Brain; Cancer Model; Carbon; Cells; Cellular Metabolic Process; Clinical; Demyelinations; Detection; Development; Diagnosis; Disease; Disease Progression; Disease model; Ensure; Evaluation; Event; Excitatory Amino Acid Transporter 2; Functional disorder; Glutamate Metabolism Pathway; Glutamates; Goals; Human; Image; Imaging Techniques; Immune; Immune System Diseases; Immune response; Immune system; Immunologic Monitoring; Immunology; Immunology procedure; Impairment; In Situ; Inflammation; Inflammatory; Innate Immune Response; Innate Immune System; Investigation; Knowledge; Label; Lesion; Lesion by Stage; Link; Lymphoid Tissue; Magnetic Resonance Imaging; Measures; Mentors; Metabolic; Methods; Modeling; Monitor; Multiple Sclerosis; Multiple Sclerosis Lesions; Neuraxis; Neurologic; Pathogenesis; Pathologic; Peripheral; Phase; Play; Positioning Attribute; Positron-Emission Tomography; Process; Production; Pyruvate; Reporting; Research; Role; Scientist; Specificity; Spinal Cord; T-Cell Activation; T-Lymphocyte; Techniques; Technology; Time; Tissues; Tracer; Training; Tumor-infiltrating immune cells; Work; adaptive immune response; axon injury; career; clinically relevant; clinically translatable; cytokine; design; excitotoxicity; first-in-human; imaging agent; imaging approach; imaging biomarker; imaging modality; imaging study; immune activation; immune imaging; immunoregulation; improved; in situ imaging; in vivo; innovation; macrophage; magnetic resonance spectroscopic imaging; molecular imaging; mouse model; multimodality; neuroimaging; neuroimmunology; neuroinflammation; non-invasive imaging; novel; pre-clinical; prevent; programs; progressive neurodegeneration; radiotracer; real-time images; reuptake; serial imaging; skills; success; tissue degeneration; tool; treatment response

ABSTRACT Activation of immune cells plays a critical role in initiation and progression of multiple sclerosis (MS), leading to progressive neurodegeneration of the central nervous system (CNS). While glutamate imbalance has been described in MS brains and has been proposed to contribute to axonal damage and tissue destruction, the relationships between glutamate dynamics and immune activation during disease progression remain unclear. Presently, the lack of clinically available noninvasive imaging methods to detect immune cells and glutamate metabolism limits our understanding of MS pathogenesis and monitoring of responses to therapies. Recent development of radiotracers for positron emission tomography (PET) have shown great potential for detection of cells from the immune system and for imaging glutamate reuptake by astroglial excitatory amino acid transporter-2 (EAAT2). Specifically, 2'-deoxy-2'-[18F]fluoro-9-β-D-arabinofuranosylguanine ([18F]F-AraG) enables the detection of activated T-cells in inflammatory diseases and cancer models. [18F]Fluoro- fluorenylaspartyl amide ([18F]FFAA) has demonstrated the ability to measure EAAT2 activity in the CNS. Hyperpolarized 13C magnetic resonance spectroscopic imaging (HP 13C MRSI) is an emerging imaging technique which measures enzymatic reactions in vivo in real-time. HP 13C pyruvate has been shown to detect highly glycolytic cells from the innate immune system in peripheral and CNS inflammation models. Recently, pyruvate labelled on the second carbon position, [2-13C]pyruvate, provided a new way to monitor glutamate production in the human brain. This project proposes to validate these innovative noninvasive PET and MR methods to provide a new way to investigate the relationships between innate and adaptive immune responses and glutamate dynamics in preclinical MS models. The mentored phase of this project will develop and validate new neuroimaging technologies: Aim 1 will investigate the potential of [18F]F-AraG and [18F]FFAA PET imaging to visualize activated T-cells and glutamate reuptake during disease progression. Aim 2 will develop and validate HP [2-13C]pyruvate as a method to simultaneously detect pro-inflammatory innate immune cells and determine real-time brain glutamate production. The independent phase of this project will build on these initial results and Aim 3 will evaluate the potential of this multimodal PET and MRI approach to monitor immune responses, glutamate production, and astrocyte functions following therapy. Central to the success of this proposal, Dr. Guglielmetti will have the support and guidance from an established group of experts in neuroimaging, particularly HP 13C MR technology (Dr. Myriam Chaumeil and Dr. Peder Larson) and PET imaging (Dr. Henry VanBrocklin) as well as in neuroimmunology and MS (Dr. Ari Green and Dr. Zamvil), providing her with the necessary skillsets to embark on a career as an independent scientist.

抽象的 免疫细胞的激活在多发性硬化症 (MS) 的发生和进展中发挥着关键作用，导致 中枢神经系统（CNS）进行性神经变性。虽然谷氨酸失衡已 在多发性硬化症的大脑中进行了描述，并被认为会导致轴突损伤和组织破坏， 疾病进展过程中谷氨酸动力学与免疫激活之间的关系仍不清楚。 目前临床上缺乏检测免疫细胞和谷氨酸的无创成像方法 新陈代谢限制了我们对多发性硬化症发病机制的理解和对治疗反应的监测。 正电子发射断层扫描 (PET) 放射性示踪剂的最新发展显示出巨大的潜力 检测免疫系统的细胞并对星形胶质细胞兴奋性氨基的谷氨酸再摄取进行成像 酸性转运蛋白-2 (EAAT2)。具体来说，2'-脱氧-2'-[18F]氟-9-β-D-阿拉伯呋喃鸟嘌呤 ([18F]F-AraG) 能够检测炎症性疾病和癌症模型中活化的 T 细胞。 [18F]氟- 芴基天冬酰胺 ([18F]FFAA) 已被证明能够测量 CNS 中的 EAAT2 活性。 超极化 13C 磁共振波谱成像 (HP 13C MRSI) 是一种新兴的成像技术 它实时测量体内的酶反应。 HP 13C 丙酮酸已被证明可以高度检测 外周和中枢神经系统炎症模型中来自先天免疫系统的糖酵解细胞。最近，丙酮酸 标记在第二个碳位置[2-13C]丙酮酸上，提供了一种监测谷氨酸生产的新方法 人类的大脑。 该项目旨在验证这些创新的无创 PET 和 MR 方法，以提供一种新的方法 研究先天性和适应性免疫反应与谷氨酸动力学之间的关系 临床前 MS 模型。该项目的指导阶段将开发和验证新的神经影像学 技术：目标 1 将研究 [18F]F-AraG 和 [18F]FFAA PET 成像可视化激活的潜力 疾病进展过程中 T 细胞和谷氨酸的再摄取。目标 2 将开发和验证 HP [2-13C]丙酮酸盐 作为一种同时检测促炎性先天免疫细胞并确定实时大脑的方法 谷氨酸生产。该项目的独立阶段将建立在这些初步成果的基础上，目标 3 将 评估这种多模式 PET 和 MRI 方法监测免疫反应、谷氨酸的潜力 治疗后的产生和星形胶质细胞功能。 Guglielmetti 博士是该提案成功的关键 将获得神经影像领域成熟专家组的支持和指导，特别是 HP 13C MR 技术（Myriam Chaumeil 博士和 Peder Larson 博士）和 PET 成像（Henry VanBrocklin 博士） 如神经免疫学和多发性硬化症（Ari Green 博士和 Zamvil 博士），为她提供了必要的技能 开始作为一名独立科学家的职业生涯。