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.

动脉粥样硬化的中央现代宗旨是炎症是该过程的关键驱动力，并且可能提供 至少对观察到的过量CVD风险的部分解释，即使在对传统风险的最佳治疗后也观察到 因素。对成像工具的不满意需要准确地将基于动脉粥样硬化的患者分层 在其炎症表型上，并确定指出给定疗法的那些表型，然后监测其作用。 单核细胞趋化蛋白1 / C-C趋化因子受体2型（MCP-1 / CCR2）轴特别是 兴趣由于其在招募促炎单核细胞中的核心作用而引起的，这些单核细胞通过其转换 促炎性巨噬细胞对于早期的动脉粥样硬化病变及其进展至关重要。我们 已经开发了一个铜-64放射性标记的细胞外环1 Inverso（ECL1I）肽PET Radiotracer， 靶标CCR2（[64cu] dota-ecl1i）。我们已经表明，这种放射性示踪剂提供了敏感和特定的检测 人单核细胞系和前体外周动脉粥样硬化中的CCR2受体表达 斑块并追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， 我们有最初的人类受试者PET数据提示[64CU] DOTA-ECL1I无创interively检测到动脉粥样硬化 病变。 我们的目标是对人类[64cu] dota-ecl1i的成像性能进行初步评估 颈动脉和股动脉动脉粥样硬化，并获得关键的生物学信息 未来研究设计的基础，以评估其诊断能力，预后分配和 评估新疗法。为了实现这一目标，我们将同时解决以下目的： 目标1。评估[64cu] dota-ecl1i PET/MR的性能检测CCR2+单核细胞和 接受颈动脉或股骨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AIM 1A中，我们将评估[64cu] dota-ecl1i在正常中的成像特性 志愿者（第1组）和接受CEA（第2组）或FEA（第3组）的患者。成像性能将是 通过与标准的MR读数的相关性确定 通过放射自显影和分子确定的CCR2含量/表达和炎症的测量值 分析测定。作为探索目的，我们将评估造血与 动脉粥样硬化斑块的进展。在AIM 1B中，我们将确定患者这种方法的可重复性 颈动脉和股动脉动脉粥样硬化闭塞性疾病进行了非手术治疗。 AIM 2。确定在体内人类动脉粥样硬化CEA和FEA斑块样品中的关系 在[64CU] DOTA-ECL1I结合，CCR2+细胞表达，免疫细胞组成，细胞因子之间 表达和牙菌斑的复杂性。动脉瘤通常是异质的，具有可变的内部内部区域 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 并使用自显影术，多重发射自显影来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，我们将从 目标1A和2A具有已知的合并症和外周动脉粥样硬化的风险因素，以确定 如果有特定的患者人群更可能具有更高或更低的CCR2斑块含量。 成功完成拟议的研究将允许描述CCR2表达的重要性 在人动脉粥样硬化中，特别是涉及相对研究的部位，例如外周动脉 疾病。这些结果将为更大的精确多中心研究奠定基础，以评估我们的成像 在人动脉粥样硬化中无创检测CCR2表达细胞的方法。