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：
10343745
负责人：
Steven Brody
金额：
$ 76.93万
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/10343745
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 Emission-Computed Tomography Fibrosis Fostering Gene Expression Genetic High Resolution Computed Tomography Human Image Immune Infiltration Inflammation Inflammatory Inflammatory Response Injury Interleukins Interstitial Lung Diseases Knockout Mice Lead Location Lung Lung Transplantation Lung diseases Mediating Mediator of activation protein Modeling Molecular Molecular Target Monitor Mus Nature Outcome Pathogenicity Pathologic Pathway interactions Patient Care Patient Monitoring Patient imaging Patients Pattern Peptides Pharmaceutical Preparations Pharmacology 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 Specificity Structure of parenchyma of lung Subgroup Testing Therapeutic Transcript Transplantation X-Ray Computed Tomography antagonist antifibrotic treatment base 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 macrophage molecular imaging molecular marker molecular targeted therapies monocyte mouse model multidisciplinary nintedanib non-invasive monitor profibrotic cytokine pulmonary function radiotracer response safety study targeted treatment transcriptome sequencing treatment response uptake

Address Animal Model Attenuated Biological Markers Biopsy Bleomycin Bone Marrow Cells Cessation of life Clinical Cytometry Data Detection Development Diagnosis Diagnostic Disease Emission-Computed Tomography Fibrosis Fostering Gene Expression Genetic High Resolution Computed Tomography Human Image Immune Infiltration Inflammation Inflammatory Inflammatory Response Injury Interleukins Interstitial Lung Diseases Knockout Mice Lead Location Lung Lung Transplantation Lung diseases Mediating Mediator of activation protein Modeling Molecular Molecular Target Monitor Mus Nature Outcome Pathogenicity Pathologic Pathway interactions Patient Care Patient Monitoring Patient imaging Patients Pattern Peptides Pharmaceutical Preparations Pharmacology 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 Specificity Structure of parenchyma of lung Subgroup Testing Therapeutic Transcript Transplantation X-Ray Computed Tomography antagonist antifibrotic treatment base 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 macrophage molecular imaging molecular marker molecular targeted therapies monocyte mouse model multidisciplinary nintedanib non-invasive monitor profibrotic cytokine pulmonary function radiotracer response safety study targeted treatment transcriptome sequencing treatment response uptake

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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.

概括肺纤维化是较难诊断的细胞反应不足，失调的细胞反应的结果和对待。一种常见的特发性肺纤维化（IPF）具有渐进的下坡过程。没有公认的用于诊断，治疗或疾病活动的分子生物标志物。临床医生目前依赖关于胸部计算机断层扫描（CT）和肺功能的变化以监测患者。而且，那里只有两种批准的药物疗法，并且不受分子生物标志物的指导。肺CCR2+（C-C 基序趋化因子受体2）炎症单核细胞及其病理后代，间质巨噬细胞是与肺纤维化的实验发展密切相关，在患者的肺中升高肺纤维化，并产生纤维化因子。 CCR2无效小鼠和通过 CCR2+后代巨噬细胞的缺失，强烈支持CCR2+细胞在人类疾病中的作用。这提案旨在利用基于分子的，正电子发射断层扫描（PET）诊断来检测CCR2- 纤维化患者肺部介导的炎症并开发靶向疗法。我们的多学科组已经确定，基于肽的放射性示踪剂64cu-dota-ecl1i确定了CCR2+ 动物模型中的单核细胞，在我们最近的人类阶段0/1的宠物/CT试验中具有可接受的剂量测定法成像。 CCR2+细胞与肺纤维化的已知关系以及管理的临床挑战 IPF患者，使该疾病特别适合评估放射性示踪剂。因此，我们使用了多种肺纤维化的小鼠模型表明，增加了64cu-dota-ecl1i肺摄取与 CCR2+细胞浸润和纤维化。我们的数据还表明，放射性示意剂检测到肺摄取的降低封闭白介素1b后，博来霉素诱导的纤维化是CCR2+细胞中表达的纤维化介质，用抗纤维化药物Pirfenidone治疗。 IPF患者的PILOT CCR2-PET成像显示肺增加信号，特别是在胸膜下纤维化区域。我们建议使用64cu-dota-ecl1i pet成像评估在动物模型中纤维化肺部疾病过程中CCR2+特异性炎症的调节，验证人类肺组织中CCR2细胞的检测，并评估监测患者的潜力。我们假设64CU-DOTA-ECL1I检测到与肺部相关的CCR2+细胞炎症过程纤维化，可用于监测疾病活动。具体目的是：（1）在小鼠纤维化模型中，评估临床治疗后，相对于炎症和纤维化的64CU-DOTA-ECL1I PET/CT吸收的变化抗纤维化药物和CCR2拮抗剂的分子靶向后，（2）在IPF患者中，评估 PET吸收，CT成像和临床状况之间的关系，然后验证PET的关系移植后去除的肺中CCR2介导的炎症和促纤维化基因表达的吸收。共同提供了一个平台，以获取与CCR2+单元基础有关的详细信息 IPF中的成像和对人类研究的解释可能导致IPF的靶向分子疗法。