PET Detection of CCR2 in Human Atherosclerosis

PET 检测人动脉粥样硬化中的 CCR2

• 批准号: 10361392
• 负责人: Robert J. Gropler
• 金额: $ 74.89万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10361392
• 关键词: Address; American; Anti-Inflammatory Agents; Area; Arterial Fatty Streak; Atherosclerosis; Autoradiography; Binding; Biological; Biological Assay; Bone Marrow; CCL2 gene; CCR1 gene; Cardiovascular Diseases; Carotid Arteries; Cell Line; Cells; Characteristics; Copper; Data; Detection; Diabetes Mellitus; Diagnosis; Disease; Disease Progression; Endarterectomy; Evaluation; Fluorescence-Activated Cell Sorting; Foundations; Future; Gene Expression; Hematopoiesis; Hemorrhage; Host Defense; Human; Image; Image Analysis; Imaging Device; Immune; Immunohistochemistry; Inflammation; Inflammatory; Lesion; Measurement; Mediating; Modeling; Modernization; Molecular; Molecular Profiling; Monitor; Multicenter Studies; Outcome Study; Pathway interactions; Patients; Peptides; Performance; Peripheral; Peripheral arterial disease; Phenotype; Play; Populations at Risk; Positron-Emission Tomography; Process; Prognosis; Radiolabeled; Reproducibility; Research; Reverse Transcriptase Polymerase Chain Reaction; Risk Factors; Role; Sampling; Seminal; Signal Transduction; Site; Smoking; Spleen; Thrombosis; Tissues; Volunteer Group; base; calcification; cardiovascular disorder risk; chemokine; chemokine receptor; comorbidity; cytokine; design; extracellular; femoral artery; high risk population; human subject; imaging approach; imaging study; in vivo imaging; interest; macrophage; monocyte; monocyte chemoattractant protein 1 receptor; mortality; novel therapeutics; optimal treatments; patient population; pre-clinical; radiotracer; receptor; receptor expression; recruit; risk stratification; systemic inflammatory response; targeted imaging; trafficking; transcriptomics; treatment response; volunteer

A central modern tenet of atherosclerosis is that inflammation is a key driver of the process, and likely provides at least a partial explanation for the excess CVD risk observed even after optimal treatment of traditional risk factors. There is a critical unmet need for imaging tools that accurately risk stratify atherosclerotic patients based on their inflammatory phenotype and identify those where a given therapy is indicated and then monitor its effect. The monocyte chemoattractant protein-1 / C-C chemokine receptor type 2 (MCP-1/CCR2) axis is of particular interest due to its central role in recruitment of pro-inflammatory monocytes which through their conversion of pro-inflammatory macrophages are crucial for early atherosclerotic lesion formation and its progression. We have developed a copper-64 radiolabeled extracellular loop 1 inverso (ECL1i) peptide PET radiotracer that targets CCR2 ([64Cu]DOTA-ECL1i). We have shown this radiotracer provides sensitive and specific detection of CCR2 receptor expression in a human monocytic cell line and ex-vivo human peripheral arterial atherosclerotic plaque and tracks disease progression and treatment response in pre-clinical atherosclerotic models. Moreover, we have initial human subject PET data to suggest [64Cu]DOTA-ECL1i noninvasively detects atherosclerotic lesions. Our objective is to perform the initial evaluation of the imaging performance of [64Cu]DOTA-ECL1i in humans with peripheral carotid and femoral arterial atherosclerosis and obtain key biological information that is foundational for the design of future studies to assess its capability for diagnosis, prognosis assignment and evaluation of new therapies. To achieve this objective we will address, in parallel, the following Aims: Aim 1. Evaluate the performance of [64Cu]DOTA-ECL1i PET/MR to detect CCR2+ monocytes and macrophages in atherosclerotic plaques from patients undergoing carotid or femoral endarterectomy (CEA and FEA): In Aim 1A we will evaluate the imaging characteristics of [64Cu]DOTA-ECL1i in normal volunteers (Group 1) and in patients undergoing CEA (Group 2) or FEA (Group 3). Imaging performance will be determined by correlation with standard MR readouts of plaque presence, size and stage and with ex-vivo tissue measurements of CCR2 content/expression and inflammation determined by autoradiography and molecular profiling assays. As an exploratory Aim we will assess the relationship between hematopoiesis and atherosclerotic plaque progression. In Aim 1B we will determine the reproducibility of this approach in patients with carotid and femoral artery atherosclerotic occlusive disease managed non-operatively. Aim 2. Determine in ex-vivo human atherosclerotic CEA and FEA plaque samples the relationship between [64Cu]DOTA-ECL1i binding, CCR2+ cellular expression, immune cell composition, cytokine expression and plaque complexity. Atheromas are often heterogeneous with areas of variable intraplaque calcification, hemorrhage, and inflammation. We will define lesion types with variable [64Cu]DOTA-ECL1i signal and characterize their cellular and molecular composition using autoradiography, multiplex immunohistochemistry and spatial transcriptomics. As an exploratory analysis, we will correlate findings from Aims 1A and 2A with known co-morbidities and risk factors for peripheral arterial atherosclerosis to determine if there are specific patient populations that are more likely to have higher or lower CCR2 plaque content. Successful completion of the proposed research will permit delineation of the importance of CCR2 expression in human atherosclerosis, particularly involving sites that are relatively understudied such as peripheral arterial disease. These results will lay the foundation for larger seminal multi-center studies to assess our imaging approach to noninvasively detect CCR2 expressing cells in human atherosclerosis.

动脉粥样硬化的现代核心原则是炎症是该过程的关键驱动因素，并且可能提供 即使在传统风险的最佳治疗之后，至少可以部分解释观察到的额外 CVD 风险 因素。对于基于动脉粥样硬化患者准确风险分层的成像工具存在着严重的未满足需求。 确定其炎症表型并确定适合特定治疗的患者，然后监测其效果。 单核细胞趋化蛋白-1 / C-C 趋化因子受体 2 型 (MCP-1/CCR2) 轴具有特殊作用 由于其在募集促炎性单核细胞中的核心作用而引起人们的兴趣，而促炎性单核细胞通过将促炎性单核细胞转化为 促炎巨噬细胞对于早期动脉粥样硬化病变的形成及其进展至关重要。我们 开发了一种铜 64 放射性标记的细胞外环 1 inverso (ECL1i) 肽 PET 放射性示踪剂 靶向 CCR2 ([64Cu]DOTA-ECL1i)。我们已经证明这种放射性示踪剂可以敏感且特异地检测 CCR2 受体在人单核细胞系和离体人外周动脉粥样硬化中的表达 斑块并跟踪临床前动脉粥样硬化模型中的疾病进展和治疗反应。而且， 我们拥有初始人类受试者 PET 数据表明 [64Cu]DOTA-ECL1i 可无创检测动脉粥样硬化 病变。 我们的目标是对 [64Cu]DOTA-ECL1i 在人体中的成像性能进行初步评估 与外周颈动脉和股动脉粥样硬化相关，并获得关键的生物学信息 为未来研究设计评估其诊断、预后分配和评估能力奠定基础 新疗法的评估。为了实现这一目标，我们将同时实现以下目标： 目标 1. 评估 [64Cu]DOTA-ECL1i PET/MR 检测 CCR2+ 单核细胞和 接受颈动脉或股动脉内膜切除术的患者动脉粥样硬化斑块中的巨噬细胞 （CEA 和 FEA）：在目标 1A 中，我们将评估 [64Cu]DOTA-ECL1i 在正常情况下的成像特性 志愿者（第 1 组）和接受 CEA（第 2 组）或 FEA（第 3 组）的患者。成像性能将 通过与斑块存在、大小和阶段的标准 MR 读数以及离体组织的相关性来确定 通过放射自显影和分子生物学测定 CCR2 含量/表达和炎症的测量 分析分析。作为一个探索性目标，我们将评估造血和造血之间的关系 动脉粥样硬化斑块进展。在目标 1B 中，我们将确定这种方法在患者中的重现性 患有非手术治疗的颈动脉和股动脉动脉粥样硬化闭塞性疾病。 目标 2. 确定离体人动脉粥样硬化 CEA 和 FEA 斑块样本的关系 [64Cu]DOTA-ECL1i 结合、CCR2+ 细胞表达、免疫细胞组成、细胞因子之间 表达和斑块复杂性。粥样斑块通常是异质的，斑块内区域各异 钙化、出血和炎症。我们将使用变量 [64Cu]DOTA-ECL1i 信号定义病变类型 并使用放射自显影、多重分析表征其细胞和分子组成 免疫组织化学和空间转录组学。作为探索性分析，我们将把以下发现关联起来： 目标 1A 和 2A 与已知的外周动脉粥样硬化合并症和危险因素一起确定 是否存在更可能具有更高或更低 CCR2 斑块含量的特定患者群体。 成功完成拟议的研究将能够描述 CCR2 表达的重要性 在人类动脉粥样硬化中，特别是涉及研究相对较少的部位，例如外周动脉 疾病。这些结果将为更大规模的开创性多中心研究奠定基础，以评估我们的成像 一种非侵入性检测人类动脉粥样硬化中 CCR2 表达细胞的方法。