Novel, Non-invasive Multi-spectral, Multi-compartment 129Xe MR Gas-exchange Measurements: MUCXE

超极化129Xe MRI提供了一种同时快速量化肺功能的方法，包括吸入气体通过气道的位置（通气）和气体交换发生的位置-肺泡和肺血管膜之间的界面以及毛细血管中红细胞的摄取（灌注）。这种新颖的、无创的功能性核磁共振和光谱（MRS）方法是在近30年前的一项基础研究物理发现的基础上首创的。我的研究项目侧重于发展肺部129Xe MRI和MRS采集和分析方法，以详细、机制地了解：1)肺部MRI通气及其与气道和实质结构的关系，以及2)肺部气体交换和灌注及其与末端气道和心肺血管的结构和形态的关系。我们最近发现了两项推动医学物理学研究的发现。首先，我们偶然发现了5倍超增强的129Xe MRI红细胞信号，这反映了一名无症状青少年先前沉默但严重的先天性心脏病（而不是先前模型预测的肺动脉重塑或肺动脉高压）。其次，我们首次发现，在长期感染COVID但肺功能正常的人群中，129Xe MRI检测到肺部气体交换和/或通气异常。这些MRI结果与用力性呼吸困难和去饱和高度相关，这巩固了肺部气体交换和通气异常在长途COVID中的核心作用。这些意想不到的发现导致了目前升级过时基础设施的建议，并将使我们能够提出有关体内129Xe MRI气体交换测量的生理学意义的重要问题。简而言之，我们建议建立一个生物物理模型来估计基于129Xe测量的毛细血管体积、血流量、红细胞压积、粘度、血管体积和阻抗。虽然以前的模型忽略了心脏负荷对生理变异性的贡献，但我们将模拟不同的负荷条件。这项假设驱动的研究和机制建模依赖于高通量129Xe极化（硬件和软件）和一套心肺测试设备，该设备可以探测心脏和肺部对运动输出的影响。为了升级临终设备，我们请求资助工具，以加速我们的研究，以解释和验证肺部细微异常，表现为呼吸困难和运动限制。有了这些建议的研究工具和我实验室的物理研发专业知识，实现这一目标是可能的。所要求的基础设施将在我的实验室中持续日常运行，该实验室目前由两名研究员，六名博士生，一名硕士和荣誉论文学生，三名本科生和两名工作人员组成。

Hyperpolarized 129Xe MRI provides a way to simultaneously and rapidly quantify the function of the lung including where inhaled gas travels through the airways (ventilation) AND where gas-exchange occurs - the interface between the alveolar and pulmonary vascular membranes and uptake into red blood cells (perfusion) in the capillaries. This novel, non-invasive functional MRI and spectroscopy (MRS) method was pioneered on the basis of a basic research physics discovery nearly 30 years ago. My research program focuses 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, and, 2) pulmonary gas-exchange and perfusion and their relationship with the structure and morphometry of the terminal airways and cardio-pulmonary vasculature. We recently discovered two findings that are driving this medical physics research. First, we serendipitously detected 5-fold super-enhanced 129Xe MRI red blood cell signal, which reflected previously silent but serious congenital heart disease in an asymptomatic teenager (and not pulmonary artery remodelling or pulmonary hypertension predicted in previous models). Second, we showed for the first time that in people with long-haul COVID but normal pulmonary function, 129Xe MRI detected pulmonary gas-exchange and/or ventilation abnormalities. These MRI findings were highly correlated with exertional dyspnea and desaturation which has cemented the role of pulmonary gas-exchange and ventilation abnormalities as central to long-haul COVID. These unexpected findings led to the current proposal to upgrade obsolete infrastructure and would allow us to ask important questions about the physiologic meaning of invivo 129Xe MRI gas-exchange measurements. Briefly, we propose to develop a biophysical model to estimate capillary volume, blood flow, hematocrit, viscosity, vessel volume, impedance based on 129Xe measurements. Whilst previous models have ignored cardiac workload contributions to physiologic variability, we will model diverse workload conditions. This proposed hypothesis-driven research and mechanistic modelling is dependent on high throughput 129Xe polarization (hardware and software) and a suite of cardiopulmonary testing equipment which probes cardiac and pulmonary influences on exercise output. To upgrade end-of-life equipment, we request funding for tools that will accelerate our research towards our goal of explaining and validating subtle abnormalities in the lung that manifest as dyspnea and exercise limitation. With these proposed research tools and my lab's physics R&D expertise, the accomplishment of this goal is possible. The requested infrastructure will be in continuous daily operation in my lab which currently consists of two fellows, six PhD students, a single MSc and honours thesis student, three undergrads and two staff researchers.