Imaging Activated Macrophages in the Lungs

 描述(申请人提供)：持续和/或调节失调的巨噬细胞激活在包括慢性阻塞性肺疾病(COPD)在内的多种炎症性肺部疾病的发病机制中发挥关键作用。使用非侵入性方法对激活的巨噬细胞进行成像将允许经常监测疾病进展和对治疗的反应。在本研究的第一阶段，我们致力于发展基于激活的巨噬细胞表达叶酸受体β(FRβ)的光学和核成像策略。在肺部炎症的背景下，我们发现巨噬细胞和单核细胞中共表达高水平炎症细胞因子的FRβ表达显著增加。在初步数据中，我们显示慢性阻塞性肺疾病的慢性呼吸道炎症导致表达FRβ的巨噬细胞显著增加。在慢性阻塞性肺疾病患者经支气管肺泡灌洗获得的肺巨噬细胞中，大约50%表达FRβ，而健康人的巨噬细胞中只有10%表达FRβ。在这项提案中，我们将检验这样一种假设，即使用正电子发射断层扫描(PET)检测激活的巨噬细胞的基于叶酸的分子成像可以识别COPD患者，并确定那些最有可能因慢性肺部炎症水平较高而快速疾病进展的患者。设计的具体目标是：1)在COPD小鼠模型中验证基于叶酸的PET探针，2)在啮齿动物和人类中使用基于叶酸的PET探针进行剂量、毒理学和安全性研究，以及3)测试基于叶酸的PET成像是否可以用于识别COPD患者，并确定PET信号是否与炎症、疾病严重性和疾病进展速度的测量相关。初步研究将优化我们目前的叶酸-PET探针，并确定激活的巨噬细胞的PET成像是否可以用于识别COPD小鼠模型的疾病进展。随后，将在啮齿类动物和人类身上进行剂量和毒理学研究，然后在人类身上进行第一阶段研究，比较患有COPD的人和没有肺部疾病的对照组。在这项研究中，我们将与EDRN赞助的一项正在进行的研究合作，该研究旨在对肺癌风险队列进行纵向评估。PET成像将在预定的支气管镜检查之前进行，支气管镜检查作为该队列的后续评估的一部分完成。影像数据将与BAL中的炎症参数以及疾病严重程度和进展的生理测量相关联。总之，这些研究将确定基于叶酸的成像是否有助于量化COPD等肺部疾病的炎症，以及识别巨噬细胞激活是否可以确定将受益于抗炎或巨噬细胞靶向治疗的患者亚群。(摘要结束)

 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)