Grant: Discovery Grants Program - Individual

Hyperpolarized 129Xe MRI provides a novel, high spatial resolution and rapid approach for simultaneously quantifying the function of the individual compartments of the respiratory system. This includes spatially and quantitatively measuring where inhaled gas travels through the airways (ventilation) AND where gas-exchange occurs - the interface between the alveolar and pulmonary vascular membranes (membrane signal) and uptake into red blood cells (perfusion) in the pulmonary vascular capillaries. This non-invasive functional MRI and spectroscopy (MRS) method was pioneered on the basis of basic research physics discoveries. Our recent 129Xe MR spectroscopy and imaging developments, funded by my previous NSERC awards have resulted in disruptive discoveries that have led to this proposal. My research team has been focused on the development of pulmonary 129Xe MRI and MRS acquisition and analysis methods towards a detailed, mechanistic understanding of: 1) pulmonary MRI ventilation and its relationship with airway and parenchyma structure, 2) pulmonary gas-exchange and perfusion and their relationship with the structure and morphometry of the terminal airways, and, 3) pulmonary gas-exchange measurements and their relationship with the cardio-pulmonary vasculature. Our recent discoveries have modified or shifted our understanding of the physical, physiological and physics meaning of 129Xe MRI gas-exchange measurements. Our preliminary evidence strongly supported the notion that both pulmonary gas-exchange and ventilation abnormalities were highly correlated with exertional dyspnea and post-exertional desaturation which has cemented the role of MRI abnormalities as central to a number of pulmonary conditions, including long-COVID. Here we propose to develop novel 129Xe MRI and MRS measurements and then develop biophysical models to estimate and validate non-invasive measurements of capillary volume, blood flow, hematocrit, viscosity, vessel volume and impedance. Whilst previous models have ignored cardiac workload contributions to physiologic variability, we will model diverse workload and health conditions. This is important because sensitive 129Xe MRS measurements of gas-exchange are currently revealing abnormalities in the context of normal pulmonary function and chest CT imaging. It still remains a mystery what these measurements mean! Our proposed hypothesis-driven research and mechanistic modelling will accelerate our overarching goal of explaining and validating subtle abnormalities in the lung that may manifest as dyspnea and exercise limitation and that can only be detected using 129Xe MRI and MRS. The requested support will help fund 25 undergraduate and graduate student trainees. The final suite of biophysical models resulting from this work will serve as ground truth for international investigations and the development of a deeper and mechanistic understanding of 129Xe MR gas-exchange abnormalities.