PET Detection of CCR2 in Human Atherosclerosis

PET 检测人动脉粥样硬化中的 CCR2

• 批准号: 10091521
• 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/10091521
• 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.

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