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Molecular Imaging CCR2 Lung Inflammation and Fibrosis

分子影像 CCR2 肺部炎症和纤维化

基本信息

批准号：
10543473
负责人：
Steven Brody
金额：
$ 77.25万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-02-05 至 2025-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10543473
关键词：
Address Animal Model Attenuated Biological Markers Biopsy Bleomycin Bone Marrow Cells Cessation of life Clinical Cytometry Data Detection Development Diagnosis Diagnostic Disease Fibrosis Fostering Gene Expression Genetic High Resolution Computed Tomography Human Image Immune Infiltration Inflammation Inflammatory Inflammatory Response Injury Interleukins Interstitial Lung Diseases Knockout Mice Location Lung Lung Transplantation Lung diseases Macrophage Mediating Mediator Modeling Molecular Molecular Target Monitor Mus Nature Outcome Pathogenicity Pathologic Pathway interactions Patient Care Patient Monitoring Patient imaging Patients Pattern Peptides Pharmaceutical Preparations Pharmacotherapy Phase Phase 0/1 Trial Phenotype Pirfenidone Population Positron-Emission Tomography Prediction of Response to Therapy Process Profibrotic signal Pulmonary Fibrosis Pulmonary Inflammation Radiation Reporter Reproducibility Risk Role Severities Signal Transduction Sorting Specificity Structure of parenchyma of lung Subgroup Testing Therapeutic Transcript Transplantation X-Ray Computed Tomography antagonist antifibrotic treatment bone cell cellular imaging chemokine receptor chest computed tomography clinical effect dosimetry fibrotic lung fibrotic lung disease first-in-human human disease idiopathic pulmonary fibrosis image guided imaging study indium-bleomycin interstitial irradiation lung development lung injury molecular imaging molecular marker molecular targeted therapies monocyte mouse model multidisciplinary nintedanib non-invasive monitor pharmacologic profibrotic cytokine pulmonary function radiotracer response safety study targeted treatment transcriptome sequencing treatment response uptake

项目摘要

SUMMARY Pulmonary fibrosis is the result of a poorly understood, dysregulated cellular response that is difficult to diagnose and treat. A common form, idiopathic pulmonary fibrosis (IPF), has a progressive, downhill course. There are no well-established molecular biomarkers for diagnosis, treatment, or disease activity. Clinicians currently depend on changes in chest computed tomography (CT) and pulmonary function to monitor patients. Moreover, there are only two approved drug therapies, and treatment is not guided by molecular biomarkers. Lung CCR2+ (C-C motif chemokine receptor 2) inflammatory monocytes and their pathologic progeny, interstitial macrophages, are strongly associated with the experimental development of lung fibrosis, elevated in the lungs of patients with pulmonary fibrosis, and produce profibrotic factors. Fibrosis is significantly attenuated in Ccr2 null mice and by deletion of CCR2+ progeny macrophages, strongly supporting a role for CCR2+ cells in human disease. This proposal aims to utilize a molecular, positron-emission tomography (PET)-based diagnostic to detect CCR2- mediated inflammation in the lungs of patients with fibrosis and to develop targeted therapies. Our multidisciplinary group has established that a peptide-based radiotracer, 64Cu-DOTA-ECL1i, identifies CCR2+ monocytes in animal models and has acceptable dosimetry in our recent human Phase 0/1 trial of PET/CT imaging. The known relationship of CCR2+ cells to pulmonary fibrosis and the clinical challenges of managing patients with IPF, make this disease particularly suited for evaluating the radiotracer. Therefore, we have used multiple mouse models of lung fibrosis to show that increased 64Cu-DOTA-ECL1i lung uptake correlates with CCR2+ cell infiltration and fibrosis. Our data also show that the radiotracer detects decreases in lung uptake in bleomycin-induced fibrosis after blockade of interleukin-1b, a mediator of fibrosis expressed in CCR2+ cells, and treatment with anti-fibrotic drug, pirfenidone. Pilot CCR2-PET imaging of patients with IPF show increased lung signal, particularly in regions of subpleural fibrosis. We propose to use 64Cu-DOTA-ECL1i PET imaging to evaluate modulation of CCR2+-specific inflammation during the course of fibrotic lung disease in animal models, validate the detection of CCR2 cells in human lung tissue, and assess the potential for monitoring patients. We hypothesize that 64Cu-DOTA-ECL1i detects the CCR2+ cell inflammatory process associated with pulmonary fibrosis and can be used to monitor disease activity. Specific aims are: (1) In mouse fibrosis models, assess the change in the 64Cu-DOTA-ECL1i PET/CT uptake relative to inflammation and fibrosis upon treatment with clinical anti-fibrotic drugs and following molecular targeting with CCR2 antagonists, and (2) In patients with IPF, assess the relationship between PET uptake, CT imaging, and clinical status, then validate the relationship of PET uptake with CCR2-mediated inflammation and pro-fibrotic gene expression in lungs removed after transplant. Together, the aims provide a platform to obtain detailed information related to the underpinnings of CCR2+ cell imaging in IPF and the interpretation of human studies that may lead to targeted molecular therapies for IPF.

总结