SUMMARY Hyperpolarized 129Xe MRI of the lung with polarized gases is capable of providing valuable regional information about ventilation and gas exchange that is unobtainable using other imaging modalities. However, current HP 129Xe MRI is limited by the fact that imaging takes place during a non-physiological breath-hold. In this project, we propose to develop a technique to dynamically image the lung using 129Xe MRI during free-breathing; in addition to enabling a more physiologically relevant assessment of lung function, this method will be feasible in patient populations that have thus far been inaccessible to 129Xe MR imaging due to poor breath-hold tolerance: young children, end-stage lung disease, etc. To enable the repeatable lung function measurements during free-breathing, we will construct and optimize a system to automatically deliver a small fixed volume (~50 ml, proportionally delivered based on inhaled gas flow) of 129Xe at a constant rate with each breath, via a small tube connected to a sealed facemask worn by the subject. This set-up will allow us to implement a breathing / imaging protocol that requires no subject effort or training, and is therefore more compatible with widespread clinical implementation. Using a novel 3D spiral acquisition designed to optimize signal, navigator fidelity, and resolution of spectral components, we will acquire a number of novel imaging parameters capable of assessing specific lung regions' dynamical behavior over the course of a breathing cycle. Finally, we will establish the reproducibility and sensitivity of these markers to early smoking- induced changes in lung function via imaging in both healthy subjects and at-risk smokers. While the studies proposed in this project focus on assessing functional alterations indicative of early COPD, the dynamic imaging technique we propose to develop has several other potential clinical applications. Most notably, these include conditions (e.g., unexplained dyspnea, long COVID) in which the aspect of lung function limiting gas exchange is unknown, and clinical syndromes (like COPD) in which disparate pathophysiology requires an assessment tool with broad sensitivity to identify and classify functional change in early disease.