Imaging Activated Macrophages in the Lungs

肺部活化巨噬细胞成像

• 批准号: 9338287
• 负责人: Timothy S. Blackwell
• 金额: $ 70.35万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 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/9338287
• 关键词: Acute; Aging; Anti-Inflammatory Agents; Anti-inflammatory; Automobile Driving; Binding; Biological Availability; Bronchoalveolar Lavage; Bronchoscopy; Cells; Chronic; Chronic Obstructive Airway Disease; Data; Development; Disease; Disease Progression; Disease model; Dose; Drug Delivery Systems; Drug Kinetics; Early Detection Research Network; Enrollment; Escherichia coli; Evaluation; Fluorescent Probes; Folic Acid; Future; Host Defense; Human; Image; Individual; Inflammation; Inflammatory; Investigation; Investigational New Drug Application; Lead; Lipopolysaccharides; Lung; Lung Inflammation; Lung diseases; Macrophage Activation; Malignant neoplasm of lung; Matrix Metalloproteinases; Measurement; Mediator of activation protein; Methods; Microbe; Monitor; Mus; Particulate; Pathogenesis; Patients; Performance; Phase; Phenotype; Physiological; Play; Population; Positron-Emission Tomography; Production; Radiolabeled; Radiopharmaceuticals; Rattus; Reactive Oxygen Species; Research Design; Respiratory physiology; Risk; Rodent; Schedule; Severity of illness; Signal Transduction; Subgroup; Testing; Toxicology; Tracer; Transgenic Organisms; airway inflammation; analog; base; cigarette smoke-induced; cohort; cyanine dye 5; cytokine; design; drug metabolism; folate-binding protein; follow-up; human subject; imaging approach; in vivo; inflammatory lung disease; longitudinal design; macrophage; molecular imaging; monocyte; mouse model; novel; nuclear imaging; optical imaging; phase 1 study; precision medicine; pulmonary function; pulmonary function decline; response; safety study; safety testing; single photon emission computed tomography; targeted treatment; treatment response; uptake

 DESCRIPTION (provided by applicant): Persistent and/or dysregulated macrophage activation plays a key role in the pathogenesis of multiple inflammatory lung diseases, including chronic obstructive pulmonary disease (COPD). Imaging activated macrophages using a non-invasive approach would allow frequent monitoring of disease progression and response to therapy. In the first phase of this RFA, we focused on developing optical and nuclear imaging strategies based on expression of folate receptor β (FRβ) by activated macrophages. In the setting of lung inflammation, we showed markedly increased FRβ expression in macrophages and monocytes that co- expressed high levels of inflammatory cytokines. In preliminary data, we showed that chronic airway inflammation in COPD results in a dramatic increase in FRβ-expressing macrophages. In lung macrophages obtained by bronchoalveolar lavage (BAL) from COPD patients, approximately 50% express FRβ, whereas only <10% of macrophages from healthy controls express FRβ. In this proposal, we will test the hypothesis that folate-based molecular imaging using positron emission tomography (PET) to detect activated macrophages can identify COPD patients and determine those most likely to have rapid disease progression due to higher levels of chronic lung inflammation. Specific aims are designed to: 1) validate folate-based PET probes in mouse models of COPD, 2) perform dosing, toxicology, and safety studies with folate-based PET probes in rodents and humans, and 3) test whether folate-based PET imaging can be used to identify COPD patients and determine whether the PET signal correlates with measurements of inflammation, disease severity, and rate of disease progression. Initial studies will optimize our current folate-PET probes and determine whether PET imaging of activated macrophages can be used to identify progression of disease in mouse models of COPD. Subsequently, dosing and toxicology studies will be performed in rodents and humans, followed by a Phase I study in humans comparing individuals with COPD to control subjects without lung disease. For this investigation, we will partner with an ongoing EDRN-sponsored study designed for longitudinal evaluation of a cohort at risk for lung cancer. PET imaging will be performed prior to scheduled bronchoscopy, which is completed as part of the follow-up evaluation in this cohort. Imaging data will be correlated with parameters of inflammation in BAL and physiologic measurements of disease severity and progression. Together, these studies will determine whether folate-based imaging is useful for quantifying inflammation in lung diseases like COPD, and whether identifying macrophage activation could delineate a subgroup of patients who would benefit from anti-inflammatory or macrophage-targeted therapies. (End of Abstract)

 描述（由适用提供）：持续性和/或失调的巨噬细胞激活在多种炎症性肺部疾病（包括慢性阻塞性肺疾病（COPD））的发病机理中起关键作用。使用非侵入性方法进行成像激活的巨噬细胞将允许经常监测疾病进展和对治疗的反应。在此RFA的第一阶段，我们专注于基于活化巨噬细胞的叶酸受体β（FRβ）的表达制定光学和核成像策略。在肺部感染的情况下，我们在巨噬细胞和单核细胞中表现出明显增加的FRβ表达，这些表达共表达了高水平的炎性细胞因子。在初步数据中，我们表明COPD中的慢性气道注射导致表达FRβ的巨噬细胞的急剧增加。在COPD患者的支气管肺泡灌洗（BAL）获得的肺巨噬细胞中，约有50％的表达FRβ，而健康对照的巨噬细胞中只有<10％的巨噬细胞表达FRβ。在此提案中，我们将检验以下假设：基于叶酸的分子成像使用二极管发射断层扫描（PET）检测活化的巨噬细胞可以鉴定COPD患者，并确定由于慢性肺部感染水平较高而导致的疾病最有可能快速疾病的患者。具体目的旨在：1）在COPD的小鼠模型中验证基于叶酸的PET问题，2）进行剂量，毒理学和安全性研究，并在啮齿动物和人类中进行基于叶酸的PET问题，以及3）测试是否可以使用基于叶酸的PET成像来识别COPD患者并确定宠物信号与炎症，疾病严重性和疾病进展的测量是否相关。初步研究将优化我们当前的叶酸-PET探针，并确定活化巨噬细胞的PET成像是否可用于鉴定COPD小鼠模型中疾病的进展。随后，将在啮齿动物和人类中进行剂量和毒理学研究，然后在人类中进行I阶段研究，将COPD的个体与控制受试者进行无肺疾病的受试者进行比较。在这项研究中，我们将与正在进行的EDRN赞助的研究合作，旨在纵向评估患有肺癌风险的队列。 PET成像将在预定的支气管镜检查之前进行，该支气管镜检查是该队列中后续评估的一部分完成的。成像数据将与BAL中感染的参数以及疾病严重程度和进展的生理测量有关。总之，这些研究将确定基于叶酸的成像是否有助于量化COPD等肺部疾病的感染，以及鉴定巨噬细胞激活是否可以描绘出将受益于抗炎或巨噬细胞靶向疗法的患者的亚组。 （抽象的结尾）