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Principal Investigator: Robert J. Gropler
Organization: WASHINGTON UNIVERSITY
Fiscal Year: 2024
Award: $715,437
Funding agency: National Heart Lung and Blood Institute
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.
Terms: <American><Anti-Inflammatories><Anti-Inflammatory Agents><Anti-inflammatory><Area><Arterial Fatty Streak><Arterial Fatty Streaks><Assay><Atheroma><Atheromatous><Atheromatous degeneration><Atheromatous plaque><Atherosclerosis><Atherosclerotic Cardiovascular Disease><Autoradiography><Binding><Bioassay><Biological><Biological Assay><Bleeding><Blood monocyte><Body Tissues><Bone Marrow><Bone Marrow Reticuloendothelial System><C-C CKR-1><C-C Chemokine Receptor Type 1><CC chemokine receptor 1><CC-CKR-1><CCL2><CCL2 gene><CCR-1><CCR1><CCR1 gene><CCR1 receptors><CCR2 receptor><CKR-1><CMKBR1><CMKR1><CMKR1 Gene><Calcified><Cardiovascular Diseases><Carotid Arteries><Cell Body><Cell Communication and Signaling><Cell Line><Cell Signaling><CellLine><Cells><Characteristics><Chemokine (C-C Motif) Receptor 1><Chemokine Receptor Gene><Chemokine, CC Motif, Ligand 2><Chemotactic Cytokines><Copper><Cu element><Data><Detection><Diabetes Mellitus><Diagnosis><Disease Management><Disease Progression><Disorder Management><Endarterectomy><Evaluation><Femur><Fluorescence Activated Cell Sorting Fractionation><Fluorescence-Activated Cell Sorting><Fluorescence-Activated Cell Sortings><Foundations><Future><Gene Expression><Groups at risk><HM145><Hematopoiesis><Hematopoietic Cellular Control Mechanisms><Hemorrhage><Homologous Chemotactic Cytokines><Host Defense><Human><Image><Image Analyses><Image Analysis><Imaging Device><Imaging Instrument><Imaging Tool><Immune><Immunes><Immunohistochemistry><Immunohistochemistry Cell/Tissue><Immunohistochemistry Staining Method><Inflammation><Inflammatory><Intercrines><Intracellular Communication and Signaling><LD78 Receptor><Lesion><MCAF><MCP-1><MCP-1 receptor><MCP1><MIP-1 Alpha-R><MIP-1Alpha-R><MIP1aR><Macrophage><Macrophage Inflammatory Protein-1 Alpha Receptor><Marrow monocyte><Measurement><Mediating><Modeling><Modern Man><Modernization><Molecular><Molecular Fingerprinting><Molecular Interaction><Molecular Profiling><Monitor><Monocyte Chemoattractant Protein-1><Monocyte Chemotactic Protein-1><Monocyte Chemotactic and Activating Factor><Monocyte Chemotactic and Activating Protein><Monocyte Chemotactive and Activating Factor><Monocyte Secretory Protein JE><Multi-center studies><Multicenter Studies><Mφ><Non-Invasive Detection><Noninvasive Detection><Outcome Study><PET><PET Scan><PET imaging><PETSCAN><PETT><Pathway interactions><Patients><People at risk><Peptides><Performance><Peripheral><Peripheral arterial disease><Persons at risk><Phenotype><Play><Populations at Risk><Positron Emission Tomography Medical Imaging><Positron Emission Tomography Scan><Positron-Emission Tomography><Process><Prognosis><RANTES Receptor Gene><RANTES-R><RT-PCR><RTPCR><Rad.-PET><Radioautography><Radiolabeled><Receptor Protein><Reproducibility><Research><Reverse Transcriptase Polymerase Chain Reaction><Risk Factors><Role><SCYA2><SIS cytokines><Sampling><Seminal><Signal Transduction><Signal Transduction Systems><Signaling><Site><Small Inducible Cytokine A2><Smoking><Spleen><Spleen Reticuloendothelial System><Strains Cell Lines><Thrombosis><Tissues><atheromatosis><atherosclerosis plaque><atherosclerotic disease><atherosclerotic lesions><atherosclerotic plaque><atherosclerotic vascular disease><biologic><biological signal transduction><blood cell formation><blood loss><calcification><cardiovascular disease risk><cardiovascular disorder><cardiovascular disorder risk><chemoattractant cytokine><chemokine><chemokine receptor><co-morbid><co-morbidity><comorbidity><cultured cell line><cytokine><design><designing><diabetes><extracellular><femoral artery><high risk group><high risk individual><high risk people><high risk population><human subject><image evaluation><image interpretation><imaging><imaging approach><imaging based approach><imaging in vivo><imaging study><in vivo imaging><interest><molecular profile><molecular signature><monocyte><monocyte chemoattractant protein 1 receptor><mortality><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><optimal therapies><optimal treatments><pathway><patient population><peripheral artery disease><positron emission tomographic (PET) imaging><positron emission tomographic imaging><positron emitting tomography><pre-clinical><preclinical><radiolabel><radiolabeling><radiolabels><radiologically labeled><radiotracer><receptor><receptor expression><recruit><response to therapy><response to treatment><reverse transcriptase PCR><risk stratification><social role><stratify risk><systemic inflammation><systemic inflammatory response><targeted imaging><therapeutic response><therapy response><thrombotic disease><thrombotic disorder><trafficking><transcriptomics><treatment response><treatment responsiveness><volunteer><vulnerable plaque>