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

 描述(申请人提供)：囊性纤维化(CF)是一种威胁生命的遗传性疾病，在美国约有30,000名儿童和成年人受到影响。囊性纤维化跨膜传导调节因子(CFTR)基因的基因突变会导致体内产生异常粘稠的粘液，从而阻塞肺部呼吸道并促进感染。CF新疗法发展的一个主要障碍是，从常规肺功能测试中检测到的变化，如用力呼气量的减少，或CT成像的结构变化，是渐进的，而不是特异的。这需要大规模和长期的临床试验来证明新疗法的治疗效果。需要新的针对CF的生物标志物，能够提供治疗效果的快速结果指标。其中一个这样的生物标志物是液体上皮吸收(LA)，最近显示，与非CF对照组相比，成人和儿童CF受试者的液体上皮吸收(LA)均升高。然而，目前对LA的测量使用双重放射性核素闪烁成像(二维成像)，这是一种在空间和数量上都有限的方法，无法评估在疾病进展的早期阶段最受影响的较小呼吸道的变化。我们团队开发了两项互补技术，可以结合起来改善对CF患者的诊断和治疗监测。在MGH，我们首创了使用正电子发射断层扫描(PET)测量气溶胶沉积和肺功能的3D动力学工具。在麻省理工学院，我们开发了一种新的成像技术(多路传输PET，MPET)，以高灵敏度和空间分辨率在体内同时对两种PET示踪剂进行动态成像。我们的假设是，这些技术的结合使用将使肺中LA的前所未有的定量测量成为可能，提供了一种即使在较小的呼吸道也可以检测和量化这种生物标记物的变化的方法。为了测量LA，我们建议使用吸入小的放射性示踪剂(13N-NH3)和大的放射性示踪剂(76Br标记的白蛋白微团聚体)后同时获得的肺动态PET图像。将根据两种放射性示踪剂的局部传输速率的差异来计算LA，这将通过对MPET提供的两组不同的动态图像进行动态分析来获得。本研究旨在证明利用MPET定量测定动物体内LA和MCT的可行性，最终目的是开发一种快速监测CF治疗效果的临床方法。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，如非慢性支气管扩张症、慢性阻塞性肺疾病(COPD)和哮喘，在这些疾病中已经发现了CFTR基因的突变。

 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.