PI: Timothy Corcoran and Robert Parker
Title: Building Multilevel Models of Therapeutic Response in the Lungs
Description: The goal of this research is to develop a series of interconnected models of therapeutic response in the diseased lung, focused primarily on cystic fibrosis (CF), that will ultimately provide a means for predicting in vivo response based on patient-specific in vitro testing, allowing for the optimization and personalization of therapies. Our center has an extensive history with the use of human bronchial epithelial (HBE) and more recently human nasal epithelial (HNE) cell cultures to study CF pathophysiology. We have also developed functional imaging biomarkers in the lung that provide organ level quantification of CF lung physiology (mucociliary clearance and airway liquid absorption). More recently we have developed in silico systems models of lung physiology at both the cell and organ level. The in silico models provide a framework of differential equations that describe how basic physiological processes interact and contribute to experimental outcomes. Their use allows these mechanisms to be more specifically differentiated. Here we propose to link in vitro and in vivo response by sampling and culturing human nasal epithelial (HNE) cell cultures from both non-CF and CF subjects who will also perform a series of physiological assessments, including functional imaging scans. Our in silico models will facilitate this linking of these models. We wil also retrospectively and prospectively survey clinical data from donors to determine which measures of cell and organ level physiology will predict the clinical course of CF lung disease.
When developing new medications for lung diseases like cystic fibrosis, we depend on lab experiments using cells from the airways, physiology studies of how the lungs change when a drug is given and clinical studies that determine how drugs affect overall health. We want to develop computer models that will let us link the results of these different kinds of studies so that we can better predict how patients will respond to drugs by just doing lab studies on cell samples from their noses. This will allow us to develop medications more raTimothy pidly for all patients and also to personalize treatments for individual patients as well. I order to develop these computer models we will perform a series of tests on patients who have CF. This will include sampling cells from the nose and measuring their lung physiology using a combination of different imaging, breathing, and other studies performed both before and after they take a therapy. We will perform similar tests on people who do not have CF, and also studies on the parents of our CF patients who carry a single CF gene because this will provide us with information on how specific genes might affect CF lung disease. We will also look at the long term health of the CF patients and see what measured values predicted whether they became sick of stayed healthy. We will use the first half of our data to produce the computer models and the second half of our data to test their predictive accuracy.
Source: National Heart, Lung, and Blood Institute
Term: 09/01/16 – 06/30/20
Amount: $457,382 per year