3D assessment of airway liquid absorption and muco-ciliary transport: key markers of lung disease pathophysiology

 描述（由申请人提供）：囊性纤维化（CF）是一种危及生命的遗传性疾病，影响美国约30，000名儿童和成人。CF是由囊性纤维化跨膜传导调节因子（CFTR）基因的基因突变引起的，该基因突变导致身体产生异常粘稠的粘液，从而阻塞肺气道并促进感染。开发CF新疗法的主要障碍是从常规肺功能测试检测到的变化，例如用力呼气量减少或CT成像中的结构变化，是逐渐的且不特异性的。这需要大量和长期的临床试验来证明新疗法的治疗效果。需要新的CF特异性生物标志物，能够提供治疗疗效的快速结果测量。一种这样的生物标志物是液体上皮吸收（LA），最近显示与非CF对照相比，在成人和儿童CF受试者中均升高。然而，目前LA的测量使用双放射性核素肺动脉造影（二维成像），这是一种空间和定量受限的方法，无法评估在疾病进展的早期阶段受影响最大的较小气道的变化。我们的团队已经开发了两种互补的技术，可以结合起来改善CF患者的诊断和治疗监测。在MGH，我们率先开发了3D动力学工具，使用正电子发射断层扫描（PET）测量气溶胶沉积和肺功能。在麻省理工学院，我们开发了一种新的成像技术（多路PET，mPET），用于同时动态成像的两个PET示踪剂在体内具有高灵敏度和空间分辨率。我们的假设是，这些技术的组合使用将使前所未有的定量测量LA在肺部，提供一种手段来检测和量化这种生物标志物的变化，即使在较小的气道。为了测量LA，我们建议使用吸入小放射性示踪剂（13 N-NH3）和大放射性示踪剂（76 Br标记的白蛋白微聚集体）后获得的肺部动态PET图像，小放射性示踪剂（13 N-NH3）通过LA和粘膜纤毛转运（MCT）转运，大放射性示踪剂（76 Br标记的白蛋白微聚集体）仅通过MCT转运。将根据两种放射性示踪剂的局部转运率差异计算LA，将使用mPET提供的两组单独的动态图像的kineti分析获得。本研究项目旨在证明利用mPET定量测量动物LA和MCT的可行性，最终目标是开发一种快速监测CF治疗疗效的临床方法。更广泛地说，该项目的最高回报可能来自于在更普遍的肺部疾病中使用新方法获得的生理学见解，如非CF支气管扩张症，慢性阻塞性肺病（COPD）和哮喘，其中CFTR基因的突变已经被确定。

 DESCRIPTION (provided by applicant): Cystic fibrosis (CF) is a life-threatening genetic disease that affects around 30,000 children and adults in the US. CF is caused by a genetic mutation of the cystic fibrosis transmembrane conductance regulator (CFTR) gene that causes the body to produce unusually thick, sticky mucus, which occludes the lung airways and promotes infection. A major barrier to the development of new therapeutics for CF is that changes detected from conventional lung functional tests, such as decrease in forced expiratory volume, or structural changes in CT imaging, are gradual and not specific. This requires large and prolonged clinical trials to prove therapeutic efficacy of novel treatments. New CF-specific biomarkers are needed capable of providing rapid outcome measures of treatment efficacy. One such a biomarker is liquid epithelial absorption (LA) recently shown to be elevated in both adult and pediatric CF subjects compared with that of non-CF controls. However, the current measurement of LA uses dual radionuclide scintigraphy (two dimensional imaging), a method spatially and quantitatively limited, and unable to assess changes in smaller airways most affected in the early stages of disease progression. Our group has developed two complimentary technologies which can be combined to improve the diagnosis and therapy monitoring in CF patients. At MGH, we have pioneered 3D kinetic tools to measure aerosol deposition and lung function using Positron Emission Tomography (PET). At MIT, we developed a new imaging technique (multiplexed PET, mPET) for simultaneous dynamic imaging of two PET tracers in vivo with high sensitivity and spatial resolution. Our hypothesis is that the combined use of these technologies will enable unprecedented quantitative measurements of LA in the lungs, providing a means to detect and quantify variations of this biomarker even in the smaller airways. To measure LA we propose to use simultaneously acquired dynamic PET images of the lungs obtained after inhalation of a small radiotracer (13N-NH3), which is transported by both LA and muco-ciliary transport (MCT) and a large radiotracer (76Br-labeled albumin microagregate) that is transported exclusively by MCT. LA will be calculated based on the differences in local transport rate of both radiotracers, which will be obtained using a kineti analysis of the two separate sets of dynamic images provided by mPET. This research project aims to demonstrate the feasibility of utilizing mPET for quantitative measurements of LA and MCT in animals, with the ultimate goal of developing a clinical method for the rapid monitoring of CF therapy efficacy. More broadly, the project's highest reward may come from physiological insights gained from using the new method in more prevalent lung diseases such as non-CF bronchiectasis, chronic obstructive pulmonary disease (COPD) and asthma, in which mutations in the CFTR gene have been identified.