Studying Atherosclerosis Macrophage Dynamics by Combined PET and Fluorine-MRI

结合 PET 和氟 MRI 研究动脉粥样硬化巨噬细胞动力学

• 批准号: 10327644
• 负责人: Zahi A. Fayad
• 金额: $ 84.13万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-15 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10327644
• 关键词: Anti-Inflammatory Agents; Apolipoprotein E; Arterial Fatty Streak; Atherosclerosis; Bone Marrow; Bone Marrow Involvement; Cardiovascular Diseases; Cardiovascular system; Cells; Chronic; Clinical; Clinical Research; Complement; Complex; Data; Development; Disease Progression; Drug Kinetics; Event; Flow Cytometry; Fluorine; Foundations; Future; Goals; Hematopoietic; High Density Lipoproteins; Image; Imaging Techniques; Immune; Immunoglobulin Fragments; Immunohistochemistry; Immunologics; Immunology procedure; Immunotherapy; Impairment; Inflammation; Inflammatory; Intervention; Knowledge; Lead; Magnetic Resonance Imaging; Maps; Measures; Mediating; Morbidity - disease rate; Multimodal Imaging; Mus; Myocardial Infarction; Myocardial Ischemia; Nanoimmunotherapy; Necrosis; Organ; Outcome Study; Patients; Positron-Emission Tomography; Process; Production; Publishing; Radioimmunoconjugate; Radiolabeled; Seminal; Specificity; Spleen; Stratification; Stroke; TNF Receptor-Associated Factors; TNFRSF5 gene; TNFSF5 gene; Techniques; Thrombosis; Time; Translating; Vascular Cell Adhesion Molecule-1; Work; advanced disease; base; cardiovascular risk factor; cell motility; detection sensitivity; imaging modality; imaging platform; improved; in vivo; in vivo imaging; macrophage; mannose receptor; migration; monocyte; mortality; nanobodies; novel; novel therapeutics; pre-clinical; receptor; recruit; thrombotic complications; trafficking

PROJECT SUMMARY Atherosclerotic cardiovascular disease (CVD) is the main cause of morbidity and mortality worldwide. Thrombotic complications in atherosclerosis often lead to severe clinical events (myocardial infarction and stroke) and are mostly the consequence of active chronic vessel wall inflammation, characterized by presence of abundant plaque macrophages. Immunological studies have elucidated that macrophage dynamics in atherosclerosis is a complex systemic process which, after initial production of monocytes in the bone marrow, involves (i) monocyte egress (E) from the bone marrow and spleen, and subsequent plaque (ii) monocyte recruitment (R), resulting in increased (iii) macrophage accumulation (A). Although many different aspects of macrophage dynamics in ischemic heart disease have been elucidated, our current knowledge of the complex systemic interactions between immune organs and the vessel wall is exclusively based on snapshot immunological assays. In the absence of suitable in vivo readouts, an all-encompassing view on these different processes is difficult to acquire. The goal of our application is to develop an integrated multimodality imaging platform based on fluorine (19F) magnetic resonance imaging (MRI) and nanobody positron emission tomography (PET) that allows studying all aspects of macrophage dynamics in atherosclerosis, through the use of monocyte/macrophage-specific MRI and PET probes. We will employ these techniques to quantitatively map macrophage dynamics in atherosclerotic mice during disease progression and after novel nanoimmunotherapeutic intervention. 19F-MRI will be used to track monocyte egress (E) from the spleen, a process that happens gradually (during atherosclerosis progression) (Aim 1A). Monocyte recruitment (R) to and macrophage accumulation (A) in atherosclerotic plaques will be instead quantified using PET imaging of radiolabeled nanobodies (antibody fragments with ideal pharmacokinetics for vessel wall imaging) targeted against vascular cell adhesion molecule 1 (VCAM1) (R) and macrophage mannose receptor (MMR) (A) (Aim 1B). Combined 19F-MRI and nanobody PET will be used to map macrophage dynamics during atherosclerosis progression (Aim 1C), and treatment with a novel nanoimmunotherapy based on TRAF6 inhibition - which we show to specifically impair monocyte migration - to either slow down atherosclerosis progression (Aim 2A) or induce atherosclerosis regression (Aim 2B). We foresee that our findings will set the foundation for future studies of macrophage dynamics and targeted immunotherapies in the context of plaque thrombosis and cardiovascular events, for an improved stratification of cardiovascular risk.

项目摘要 动脉粥样硬化性心血管疾病（CVD）是世界范围内发病率和死亡率的主要原因。 动脉粥样硬化中的血栓并发症经常导致严重的临床事件（心肌梗死和心肌梗塞）。 中风），并且主要是活动性慢性血管壁炎症的结果，其特征在于存在 大量的噬斑巨噬细胞。免疫学研究已经阐明， 动脉粥样硬化是一种复杂的系统性过程，在骨髓中最初产生单核细胞后， 涉及（i）单核细胞从骨髓和脾脏排出（E），以及随后的斑块（ii）单核细胞 募集（R），导致（iii）巨噬细胞积聚增加（A）。虽然许多不同的方面， 巨噬细胞动力学在缺血性心脏病已经阐明，我们目前的知识复杂 免疫器官和血管壁之间的系统性相互作用完全基于快照 免疫学测定。在没有合适的体内读数的情况下，关于这些不同的生物学特性的全面观点是不可能的。 过程很难获得。我们的应用程序的目标是开发一个集成的多模态成像 基于氟（19 F）磁共振成像（MRI）和纳米抗体正电子发射的平台 断层扫描（PET），允许研究动脉粥样硬化中巨噬细胞动力学的各个方面，通过 使用单核细胞/巨噬细胞特异性MRI和PET探针。我们将使用这些技术来定量地 动脉粥样硬化小鼠在疾病进展过程中和新治疗后的巨噬细胞动力学图 纳米免疫干预19 F-MRI将用于跟踪单核细胞从脾脏的流出（E）， 逐渐发生的过程（动脉粥样硬化进展期间）（目的1A）。单核细胞募集（R） 而动脉粥样硬化斑块中的巨噬细胞积聚（A）将改为使用PET成像定量， 放射性标记的纳米抗体（具有理想的血管壁成像药代动力学的抗体片段）靶向 抗血管细胞粘附分子1（VCAM 1）（R）和巨噬细胞甘露糖受体（MMR）（A）（Aim 1B）。联合19 F-MRI和纳米抗体PET将用于绘制动脉粥样硬化期间的巨噬细胞动力学 进展（目标1C），以及基于TRAF 6抑制的新型纳米免疫疗法的治疗-我们 显示特异性损害单核细胞迁移-减缓动脉粥样硬化进展（Aim 2A）或 诱导动脉粥样硬化消退（Aim 2B）。我们预见，我们的发现将为未来奠定基础。 在斑块血栓形成背景下的巨噬细胞动力学和靶向免疫疗法的研究， 心血管事件，用于改善心血管风险分层。