Early Detection of Changes in Pulmonary Gas Exchange by Hyperpolarized Xe MRI

描述（由申请人提供）：可以说，阻碍慢性肺部疾病治疗进展的最大差距是缺乏足够敏感、全面和无创的肺功能评估方法。在填补这一空白之前，患者将接受对他们不起作用的药物治疗，新疗法的开发将仍然昂贵、缓慢，而且基本上是不成功的。因此，我们研究的长期目标是开发和实施一种方法，对心肺功能和结构的所有相关方面进行无创和纵向成像。我们的方法使用超极化（HP） 129Xe MRI来成像通风、微观结构和气体交换。本应用程序的目的是优化我们最近展示的通过129Xe MRI在人体受试者中成像区域气体交换的能力，使用优化的方法来测量和理解静息灌注异质性，并证明这种成像方法在检测区域肺功能变化方面的敏感性比目前可能的要早得多。中心假设是，与现有手段相比，区域气体交换是肺功能早期变化的最敏感标志。提出这项研究的基本原理是，开发一种可以无创地评估区域气体交换的方法，通过提供一种可以重复使用的更敏感和更具体的测量方法，将极大地加速肺部医学的研究。因此，拟议的研究与NIH的使命有关，即通过开发和加速生物医学技术的应用来改善健康。在强大的初步数据的指导下，中心假设将通过追求三个特定目标来验证：1)优化3D血液选择性129Xe气体交换MRI； 2)建立图像可重复性作为时间，姿势和心输出量的函数；3)成像放射治疗期间区域气体交换的时间演变。与金标准相比，这些目标的完成将确立这种新方法的实用性、灵敏度和局限性，同时将其定位为肺部医学研究的敏感生物标志物。第一个目标是将目前的气体交换图像分辨率提高8倍，增加纤维化特异性，并建立控制采集的关键MR物理。第二个目标将揭示初步研究中观察到的129Xe气体交换静息非均质性的关键决定因素，并建立其可重复性。最终目标是将这些技术和发展见解结合起来，以验证129Xe MRI将比现有手段更早地检测到气体交换变化的假设。所提出的方法是创新的，因为它利用了HP 129Xe MRI的独特特性和一种创新的采集方法来成像肺部最基本的功能-气体交换。这项研究具有重要意义，因为正在开发的成像方法有望提供一个长期寻求的窗口，研究气体转移到肺微循环中，作为疾病状态变化的先兆。

DESCRIPTION (provided by applicant): Arguably the biggest gap preventing progress in treating chronic pulmonary diseases is the lack of a sufficiently sensitive, comprehensive, and non-invasive means to evaluate lung function. Until this gap is filled, patients will receive medications that don't work for them, and development of new therapies will remain expensive, slow, and largely unsuccessful. The long-term goal of our research, therefore, is to develop and implement a means to image all relevant aspects of cardiopulmonary function and structure, non-invasively and longitudinally. Our approach uses hyperpolarized (HP) 129Xe MRI to image ventilation, microstructure, and gas exchange. The objective of this application is to optimize our recently demonstrated capability to image regional gas exchange by 129Xe MRI in human subjects, to use the optimized method to measure and understand resting perfusion heterogeneity, and to demonstrate the sensitivity of this imaging approach to detect changes regional lung function much earlier than currently possible. The central hypothesis is that regional gas exchange is the most sensitive marker of early changes in pulmonary function compared to available means. The rationale for the proposed research is that developing a method that can non-invasively evaluate regional gas exchange will dramatically accelerate research in pulmonary medicine by providing a more sensitive and specific measurement that can be used repeatedly. Thus, the proposed research is relevant to that part of the NIH Mission that pertains to improving health by developing and accelerating the application of biomedical technologies. Guided by strong preliminary data, the central hypothesis will be tested by pursuing three Specific Aims: 1) Optimize 3D blood-selective 129Xe gas exchange MRI 2) Establish image reproducibility as a function of time, posture, and cardiac output, and 3) Image the temporal evolution of regional gas exchange during radiation therapy. Completion of these aims will establish the utility, sensitivity and limitations of this new method compared to gold standards, while positioning it as a sensitive biomarker for research in pulmonary medicine. The first aim is expected to improve the current gas exchange image resolution 8-fold, add specificity for fibrosis, and establish the key MR physics governing the acquisition. The second aim will uncover the key determinants of the resting heterogeneity of 129Xe gas exchange already observed in preliminary studies and establish their reproducibility. The final aim brings these technical and developmental insights together to test the hypothesis that 129Xe MRI will detect alterations in gas exchange earlier than currently available means. The proposed approach is innovative because it exploits the unique properties of HP 129Xe MRI and an innovative acquisition to image lungs' most fundamental function - gas exchange. The proposed research is significant because the imaging method being developed is expected to provide a long-sought window on gas transfer into the pulmonary microcirculation as a harbinger of changing disease status.