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.

概括肺纤维化是由于人们对细胞反应知之甚少、失调而难以诊断的结果并治疗。特发性肺纤维化 (IPF) 是一种常见的形式，具有进行性、下坡的病程。没有用于诊断、治疗或疾病活动的成熟分子生物标志物。临床医生目前依赖胸部计算机断层扫描（CT）和肺功能的变化来监测患者。而且，还有只有两种已批准的药物疗法，并且治疗不受分子生物标志物指导。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、间质巨噬细胞与肺纤维化的实验发展密切相关，在患有以下疾病的患者的肺部中升高肺纤维化，并产生促纤维化因子。 Ccr2 缺失小鼠的纤维化明显减弱 CCR2+子代巨噬细胞的缺失，有力地支持了CCR2+细胞在人类疾病中的作用。这该提案旨在利用基于分子、正电子发射断层扫描 (PET) 的诊断来检测 CCR2- 介导纤维化患者肺部炎症并开发靶向治疗。我们的多学科小组已确定基于肽的放射性示踪剂 64Cu-DOTA-ECL1i 可识别 CCR2+ 动物模型中的单核细胞，并且在我们最近的 PET/CT 人类 0/1 期试验中具有可接受的剂量测定成像。 CCR2+细胞与肺纤维化的已知关系以及治疗的临床挑战患有 IPF 的患者，使得这种疾病特别适合评估放射性示踪剂。因此，我们使用了多个肺纤维化小鼠模型表明 64Cu-DOTA-ECL1i 肺摄取增加与 CCR2+细胞浸润和纤维化。我们的数据还表明，放射性示踪剂检测到肺摄取减少阻断白细胞介素 1b（CCR2+ 细胞中表达的纤维化介质）后博莱霉素诱导的纤维化，以及用抗纤维化药物吡非尼酮治疗。 IPF 患者的初步 CCR2-PET 成像显示肺部增大信号，特别是在胸膜下纤维化区域。我们建议使用 64Cu-DOTA-ECL1i PET 成像评估动物模型纤维化肺病过程中 CCR2+ 特异性炎症的调节，验证人体肺组织中 CCR2 细胞的检测，并评估监测患者的潜力。我们假设 64Cu-DOTA-ECL1i 检测与肺相关的 CCR2+ 细胞炎症过程纤维化，可用于监测疾病活动。具体目标是：（1）在小鼠纤维化模型中，评估临床治疗后 64Cu-DOTA-ECL1i PET/CT 摄取相对于炎症和纤维化的变化抗纤维化药物和 CCR2 拮抗剂分子靶向治疗，以及 (2) 在 IPF 患者中，评估 PET摄取、CT成像和临床状态之间的关系，然后验证PET的关系移植后肺中 CCR2 介导的炎症和促纤维化基因表达的吸收。这些目标共同提供了一个平台来获取与 CCR2+ 细胞基础相关的详细信息 IPF 的成像和人体研究的解释可能会导致 IPF 的靶向分子治疗。