Cystic Fibrosis (CF) is a progressive, life-shortening autosomal recessive disease that affects more than 70,000 people worldwide. Most of the morbidity and mortality in CF is from lung disease. Through an improved understanding of the pathophysiology of CF, recent historic advances in CF therapeutics have been made, propelling CF into the era of personalized medicine. However, we currently lack physiology-based outcome measures that provide quantification of the basic elements of CF lung disease, limiting our ability to rapidly screen new therapeutics. The use of functional imaging methods is a powerful and attractive approach for assessing basic aspects of airway physiology. Our lab has unique expertise in pulmonary imaging and aerosol drug delivery and is developing a functional imaging method for detecting changes in airway liquid absorption - a critical component of CF pathophysiology that should change rapidly with therapeutic correction and that no other in vivo method is capable of measuring directly. The method is based on measuring the absorption rate of a hydrophilic, small-molecule, diethylene triamine pentaacetic acid or DTPA. We have previously demonstrated increased rates of DTPA absorption and therapeutic response to osmotic therapies in CF airway epithelial cell cultures. Using a multi-probe imaging technique novel to our lab, we have demonstrated increased rates of DTPA absorption in both adult and pediatric CF subjects, and in vivo DTPA absorption response to an osmotic therapy. Collectively, these results suggest that our technique is useful in detecting changes in ASL absorption that would accompany successful treatment in vivo. Our current technique utilizes planar (2D) imaging which provides high temporal resolution, but does not permit regional measurements nor allow for clear differentiation of alveoli and airways, which are often overlapped in 2D images. Therefore, the overall goal of this project is to adapt the technique to a 3D single-photon emission computed tomography (SPECT) imaging platform and incorporating anatomical (X-ray computed tomography [CT]) imaging, allowing improved localization of our functional measurements in the lungs. 3D SPECT-CT imaging will allow us to better differentiate airway and alveolar physiology, make regional measurements of clearance and absorption in the lungs, and study therapeutic efficacy directly at sites of disease in the lung. These methodological improvements will increase the clinical utility of our technique as a means of testing new CF therapeutics directed at small patient sub-groups. Training Plan: This proposal will provide the Dr. Locke, a postdoctoral associate, with the opportunity to lead the development of a clinically-relevant and novel imaging technique and design phantom and human studies to address the hypotheses in his proposal. Each component of the training plan, which includes project-based learning, mentoring, visits to the Cystic Fibrosis Clinic, and attending conferences, has been designed to strengthen different areas required to thrive as an imaging science in the field of pulmonary medicine. The cooperative research environment at the University of Pittsburgh, coupled with the resources and experience of Drs. Tim Corcoran, Michael Myerburg, and Joseph Pilewski, will assure the candidate's progression to an independent researcher.
Sensitive and physiology-based outcome measures that quantify basic elements of Cystic Fibrosis lung disease are needed to support the advancement of disease-modifying therapies. The proposed research promises to address this critical need by developing a quantifiable outcome measure based on functional imaging methods that reflects unique features of CF lung disease: airway hyper-absorption and impaired mucociliary clearance.
