PET IMAGING CCR2 IN LUNG INFLAMMATION

肺部炎症中 CCR2 的 PET 成像

• 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
• 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

 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（由申请人提供）：总结肺部炎症可能是急性和慢性肺部疾病最恒定的特征，免疫细胞类型已被用于尝试对患者表型进行分类。然而，可靠地检测和监测这种病理特征的能力一直是一个挑战。趋化因子引导携带其同源受体的炎性细胞群体的迁移。细胞表面趋化因子（C-C基序）受体2（CCR 2）和配体CCL 2是炎症单核细胞迁移的重要介质，并调节免疫细胞群的成熟。CCR 2/CCL 2轴在急性和慢性肺疾病中都是活跃的，例如急性肺损伤、肺移植后的原发性移植物功能障碍、哮喘和慢性阻塞性肺疾病（COPD）。我们已经确定了一个7个氨基酸的肽，ECL 1 i，它特异性地结合到CCR 2受体。当组装成放射性示踪剂时，64 Cu-DOTA-ECL 1 i在小鼠中稳定并迅速排泄。当在急性和慢性肺损伤的多种模型中进行评估时，静脉内注射64 Cu-DOTA-ECL 1 i在肺中提供了与单核细胞迁移相关的稳健的正电子发射断层扫描（PET）信号。在使用CCR 2充足和缺乏小鼠的肺部疾病临床前小鼠模型中进行的PET成像表明，64 Cu-DOTA-ECL 1 i对检测低水平炎症敏感，并特异性识别与CCR 2表达免疫细胞相关的PET信号。此外，在CCR 2水平增加的晚期COPD受试者的人肺组织中，ECL 1 i探针检测到CCR 2表达增加并结合免疫细胞，表明对人CCR 2的亲和力。我们假设64 Cu-DOTA-ECL 1 i作为一种敏感、特异和安全的放射性示踪剂，用于PET检测肺部疾病中CCR 2介导的炎症。我们的目标是（1）在小鼠肺损伤模型中测试特异性、灵敏度和稳定性，（2）表征细胞和人肺组织中与人CCR 2的结合，以及（3）在0期临床安全性试验中将64 Cu-DOTA-ECL 1 i转化为人类。我们建议，非侵入性PET成像的CCR 2在肺部可以具体表征个人的炎症状态和疾病活动。这将为急性和慢性肺部疾病的个性化管理提供一个独特的机会来定义免疫反应。(End摘要）