PET Detection of CCR2 in Human Atherosclerosis

PET 检测人动脉粥样硬化中的 CCR2

• 批准号: 9905207
• 负责人: Robert J. Gropler
• 金额: $ 76.5万
• 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/9905207
• 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; Radiolabeled; Reproducibility; Research; Reverse Transcriptase Polymerase Chain Reaction; Risk; 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; outcome forecast; patient population; pre-clinical; radiotracer; receptor; receptor expression; recruit; 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.

动脉粥样硬化的一个中心现代原则是炎症是该过程的关键驱动因素，并可能提供 至少部分解释了即使在传统风险的最佳治疗后观察到的过度CVD风险 因素对于基于动脉粥样硬化患者的准确风险分层的成像工具存在关键的未满足的需求。 对他们的炎症表型，并确定那些给定的治疗是指，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（MCP-1/CCR 2）轴是一个特殊的细胞周期。 由于其在促炎性单核细胞的募集中的中心作用， 促炎性巨噬细胞对于早期动脉粥样硬化损伤形成及其进展是至关重要的。我们 已经开发了一种铜-64放射性标记的细胞外环1反向（ECL 1 i）肽PET放射性示踪剂， 靶向CCR 2（[64 Cu] DOTA-ECL 1 i）。我们已经表明，这种放射性示踪剂提供了灵敏和特异性的检测， CCR 2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 在临床前动脉粥样硬化模型中监测斑块并跟踪疾病进展和治疗反应。此外，委员会认为， 我们有初步的人类受试者PET数据表明[64 Cu] DOTA-ECL 1 i非侵入性检测动脉粥样硬化 病变 我们的目标是对[64 Cu] DOTA-ECL 1 i在人体中的成像性能进行初步评价 外周颈动脉和股动脉粥样硬化，并获得关键的生物信息， 未来研究设计的基础，以评估其诊断能力，预后分配， 评估新疗法。为实现这一目标，我们将同时致力于以下目标： 目标1.评价[64 Cu] DOTA-ECL 1 i PET/MR检测CCR 2+单核细胞的性能， 接受颈动脉或股动脉内膜切除术患者动脉粥样硬化斑块中的巨噬细胞 (CEA和FEA）：在目标1A中，我们将评价正常人中[64 Cu] DOTA-ECL 1 i的成像特征。 志愿者（第1组）和接受CEA（第2组）或FEA（第3组）的患者。成像性能将是 通过与斑块存在、大小和阶段的标准MR读数以及与离体组织的相关性来确定 通过放射自显影和分子生物学方法测定CCR 2含量/表达和炎症 谱分析测定。作为探索性目的，我们将评估造血与 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 非手术治疗颈动脉和股动脉粥样硬化闭塞性疾病。 目标二。测定离体人动脉粥样硬化斑块标本CEA与FEA的关系 [64 Cu] DOTA-ECL 1 i结合、CCR 2+细胞表达、免疫细胞组成、细胞因子 表达和斑块复杂性。动脉粥样硬化通常是异质性的，斑块内的区域不同 钙化出血和炎症我们将使用可变[64 Cu] DOTA-ECL 1 i信号定义病变类型 并使用放射自显影、多重 免疫组织化学和空间转录组学。作为一项探索性分析，我们将从 目的1A和2A与已知的合并症和外周动脉粥样硬化的风险因素，以确定 如果有特定的患者群体更可能具有更高或更低的CCR 2斑块含量。 成功完成拟议的研究将允许描绘CCR 2表达的重要性， 在人类动脉粥样硬化中，特别是涉及相对研究不足的部位，如外周动脉， 疾病这些结果将为更大的开创性多中心研究奠定基础，以评估我们的成像 非侵入性检测人动脉粥样硬化中CCR 2表达细胞的方法。