PET IMAGING CCR2 IN LUNG INFLAMMATION

肺部炎症中 CCR2 的 PET 成像

基本信息

批准号：
9090560
负责人：
Steven Brody
金额：
$ 64.93万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-01 至 2019-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9090560
关键词：
Acute Acute Disease Acute Lung Injury Adult Respiratory Distress Syndrome Affinity Amino Acids Animal Model Animals Asthma Autoradiography Binding Bronchoscopy CCL2 gene Cell Line Cell surface Cells Chemistry Chronic Chronic Disease Chronic Obstructive Airway Disease Chronic lung disease Clinical Cryopreserved Cell Data Dendritic Cells Detection Development Diagnosis Disease Flow Cytometry Functional disorder Human Image Image Analysis Immune Immunologic Monitoring Immunologics Individual Inflammation Inflammation Mediators Inflammatory Injury Investigational New Drug Application Leukocytes Ligands Lung Lung Inflammation Lung Transplantation Lung diseases Mediating Methods Microscopy Modeling Molecular Monitor Mus Organ Pathologic Patients Peptides Phase Phase I Clinical Trials Phenotype Population Positron-Emission Tomography Procedures Production Proteins Protocols documentation Reporter Safety Sampling Sensitivity and Specificity Signal Transduction Specificity Structure of parenchyma of lung Testing Therapeutic Tissues Toxicology Translating abstracting base beta-Chemokines cell type chemokine dosimetry healthy volunteer human tissue improved outcome in vitro Assay intravenous injection lung injury migration monocyte mouse model non-invasive imaging novel novel therapeutics personalized management population migration pre-clinical quantitative imaging radiotracer receptor respiratory infection virus response safety study targeted treatment two-photon

项目摘要

DESCRIPTION (provided by applicant):Summary Lung inflammation is perhaps the most constant feature of acute and chronic lung disease, and immune cell types have been used to attempt to classify patient phenotypes. However, the ability to reliably detect and monitor this pathologic feature has been a challenge. Chemokines guide the migration of populations of inflammatory cells that harbor their cognate receptor. Cell surface chemokine (C-C motif) receptor 2 (CCR2) and ligand CCL2 are essential mediators of inflammatory monocyte migration and modulate the maturation of immune cell populations. The CCR2/CCL2 axis is active in both acute and chronic lung diseases, such as acute lung injury, primary graft dysfunction following lung transplantation, asthma and chronic obstructive pulmonary disease (COPD). We have identified a 7 amino acid peptide, ECL1i, which specifically binds to the CCR2 receptor. When assembled as a radiotracer, 64Cu-DOTA-ECL1i, was stable in mice and rapidly excreted. When assessed in multiple models of acute and chronic lung injury, intravenous injection of 64Cu- DOTA-ECL1i provided a robust positron emission tomography (PET) signal in the lung associated with monocyte migration. PET imaging in preclinical mouse models of lung disease that utilized CCR2 sufficient and deficient mice demonstrated that 64Cu-DOTA-ECL1i is sensitive for the detection of low levels of inflammation and specific for identifying PET signals related to CCR2-expressing immune cells. Moreover, in human lung tissues from subjects with advanced COPD displaying increased CCR2 levels, ECL1i probes detected increased CCR2 expression and bound immune cells, suggesting an affinity for human CCR2. We hypothesize that 64Cu-DOTA-ECL1i performs as a sensitive, specific and safe radiotracer for PET detection of CCR2- directed inflammation in lung disease. Our aims will (1) test the specificity, sensitivity and stability in mouse lung injury models, (2) characterize bindig to human CCR2 in cells and human lung tissue and (3) translate 64Cu-DOTA-ECL1i to humans in a Phase 0 clinical safety trial. We propose that non-invasive PET imaging of CCR2 in the lung can specifically characterize an individual's inflammatory status and disease activity. This will provide a unique opportunity to define the immunologic response for personalized management in acute and chronic lung diseases. (End of Abstract)

描述（由适用提供）：摘要肺部炎症可能是急性和慢性肺部疾病的最恒定特征，并且已使用免疫核管类型试图对患者表型进行分类。但是，可靠检测和监测此病理特征的能力是一个挑战。趋化因子指导植入其同源受体的炎性细胞种群的迁移。细胞表面趋化因子（C-C基序）受体2（CCR2）和配体CCL2是炎症单核细胞迁移的基本介体，并调节免疫核管种群的成熟。 CCR2/CCL2轴在急性和慢性肺部疾病中都活跃，例如急性肺损伤，肺移植后的一级移植功能障碍，哮喘和慢性阻塞性肺疾病（COPD）。我们已经确定了7个氨基酸肽ECL1I，该肽与CCR2受体特别结合。当作为放射性示例（64cu-dota-ecl1i）组装时，小鼠稳定并迅速超过。当在多种急性和慢性肺损伤的模型中评估时，静脉注射64cu- dota-ecl1i提供了与单核细胞迁移相关的肺中强大的正电子发射断层扫描（PET）信号。利用CCR2足够且缺乏小鼠的肺疾病临床前小鼠模型中的PET成像表明，64CU-DOTA-ECL1I对检测低炎症的检测很敏感，并且对于鉴定与表达CCR2表达CCR2的不经意识的PET信号的特定于敏感。此外，在患有高级COPD的受试者的人肺组织中，CCR2水平升高，ECL1I问题检测到CCR2表达增加并结合了免疫细胞，这表明对人CCR2有亲和力。我们假设64CU-DOTA-ECL1I是一种敏感，特异性且安全的放射性示踪剂，可用于检测肺部病中CCR2定向炎症。我们的目标将（1）在小鼠肺损伤模型中测试特异性，灵敏度和稳定性，（2）在细胞和人肺组织中与人CCR2的结合表征，（3）在0期临床安全试验中将64CU-DOTA-ECL1I转化为人类。我们建议，肺中CCR2的非侵入性PET成像可以特异性地表征个人的炎症状态和疾病活动。这将提供一个独特的机会，以定义急性和慢性肺部疾病个性化管理的免疫学反应。（抽象的结尾）