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

基本信息

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
项目类别：
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

项目摘要

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）的启动和进展中起着至关重要的作用，中枢神经系统（CNS）进行性神经变性。而谷氨酸不平衡在MS大脑中描述，并已被提出有助于轴突损伤和组织破坏，在疾病进展过程中，谷氨酸动力学与免疫激活之间的关系尚不清楚。目前，缺乏可检测免疫细胞和谷氨酸的临床上可用的非侵入性成像方法代谢限制了我们对MS发病机理的理解和对疗法反应的监测。阳性发射断层扫描（PET）的最新开发的放射性示例已显示出很大的潜力从免疫系统中检测细胞和用于通过星形胶质兴奋性氨基的谷氨酸重新摄取的成像酸转运蛋白-2（EAAT2）。特别是2'-脱氧2' - [18F]氟-9-β-β-β-β-d- arabinofuranosylyalguanine（[[18f] f-arag）可以在炎症性疾病和癌症模型中检测活化的T细胞。 [18f]氟 - 氟苯基酰胺基酰胺（[18F] FFAA）证明了在中枢神经系统中测量EAAT2活性的能力。超极化13C磁共振光谱成像（HP 13C MRSI）是一种新兴成像技术它实时测量体内酶促反应。 HP 13C丙酮酸已显示出高度检测来自先天性免疫系统的糖酵解细胞和中枢神经系统注射模型中的糖酵解细胞。最近，丙酮酸在第二碳位置标记[2-13c]丙酮酸，提供了一种监测谷氨酸生产的新方法人脑。该项目的建议旨在验证这些创新的无创宠物和MR方法，以提供一种新的方式研究先天和适应性免疫回报与谷氨酸动力学之间的关系临床前MS模型。该项目的修改阶段将开发并验证新的神经影像学技术：AIM 1将研究[18F] F-ARAG和[18F] FFAA PET成像的潜力以可视化激活疾病进展过程中T细胞和谷氨酸再摄取。 AIM 2将发展并验证HP [2-13C]丙酮酸作为同时检测促炎的先天免疫电池并确定实时大脑的一种方法谷氨酸生产。该项目的独立阶段将基于这些初始结果，AIM 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生产和星形胶质细胞功能。该提案成功的核心，Guglielmetti博士将得到一群神经影像专家的支持和指导，尤其是HP 13C 技术先生（Myriam Chaumeil博士和Peder Larson博士）和PET Imaging（Henry VanBrocklin博士）就像在神经免疫学和MS（Ari Green博士和Zamvil博士）中一样，为她提供必要的技能从事独立科学家的职业。