Studying Atherosclerosis Macrophage Dynamics by Combined PET and Fluorine-MRI

项目总结 动脉粥样硬化性心血管疾病是世界范围内发病率和死亡率的主要原因。 动脉粥样硬化的血栓并发症通常会导致严重的临床事件(心肌梗死和 中风)，主要是活动性慢性血管壁炎症的结果，其特征是存在 丰富的斑块巨噬细胞。免疫学研究已阐明巨噬细胞动力学 动脉粥样硬化是一个复杂的全身过程，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流出(E)，以及随后的斑块(Ii)单核细胞 募集(R)，导致(III)巨噬细胞聚集增加(A)。尽管许多不同的方面 巨噬细胞在缺血性心脏病中的动力学已被阐明，我们目前对该复合体的了解 免疫器官和血管壁之间的系统相互作用完全基于快照 免疫学检测。在没有合适的活体读数的情况下，对这些不同的 流程很难获得。我们的应用程序的目标是开发一种集成的多模式成像 基于氟(19F)磁共振成像(MRI)和纳米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方方面面，通过 使用单核/巨噬细胞特异性核磁共振和正电子发射计算机断层扫描探针。我们将使用这些技术来量化 MAP在动脉粥样硬化小鼠疾病进展过程中的巨噬细胞动力学 纳米免疫治疗干预。19F-MRI将被用来追踪单核细胞从脾中流出， 逐渐发生的过程(在动脉粥样硬化进展过程中)(目标1A)。单核细胞募集(R)至 而动脉粥样硬化斑块中的巨噬细胞聚集(A)将改为使用PET成像进行量化 靶向放射性标记纳米体(具有理想药代动力学的血管壁成像的抗体片段) 抗血管细胞黏附分子1(VCAM1)(R)和巨噬细胞甘露糖受体(A)(目的 1B)。结合19F-MRI和纳米体PET将用于绘制动脉粥样硬化期间巨噬细胞的动力学图 进展(Aim 1C)，并用一种基于TRAF6抑制的新型纳米免疫疗法治疗--我们 显示为专门损害单核细胞迁移--要么减缓动脉粥样硬化进展(目标2A)，要么 诱导动脉粥样硬化消退(目标2B)。我们预计，我们的发现将为未来奠定基础 斑块血栓形成和斑块形成的巨噬细胞动力学和靶向免疫治疗的研究 心血管事件，以改进心血管风险分层。

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.