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

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 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.