Imaging Regional Physiological and Structural Parameters of Airway Remodeling

描述(由申请人提供)：肺功能和结构的定量区域评估有可能加强肺部疾病的早期诊断和管理，并提供更有效的治疗评估。利用这笔赠款，我们的目标是开发区域定量技术，用于测量小鼠的肺功能和结构。我们将利用超极化氦-3磁共振技术来改进测量小鼠肺通气量、氧合和肺泡大小的仪器和非侵入性技术。这些成像技术的重现性和全球验证将作为该项目的一部分进行。此外，我们将系统地评估每种测量技术对小鼠哮喘炎症模型的存在和严重程度的敏感性。除了研究这些技术对呼吸道炎症反应的敏感性外，我们还将研究这些区域标志物与肺功能和结构的金标准指标(即肺功能测试和组织病理学)的相关性。哮喘固有的异质性特征表明，基于成像的肺功能和结构的区域测量可能会成为研究这种肺疾病的不同方面的更强大的工具，而通过全球肺功能测量可能无法观察到这些方面。完全控制呼吸参数并以极好的重复性重复测量的能力使小型啮齿动物的肺部成像非常有趣。这种重复性在更大的动物身上是很难达到的。然而，目前许多现有的超极化3He MRI技术--特别是用于测量PAO2的技术--并不直接适用于啮齿动物和其他小动物，因为这些物种的生理过程速度更快，如氧气耗竭速度，以及有效成像所需的呼吸长度的生理限制。因此，在肺部研究中，人们强烈感受到需要一套既定的测量工具来研究啮齿动物肺部系统的区域性方面，特别是小鼠。我们小组最近开发了克服这些挑战的方法，通过这笔赠款，我们的目标是进一步完善这些方法。这项建议的中心目标是开发、实施和改进超极化气体磁共振成像技术，以测量健康小鼠肺内的局部肺通气量(VA)、氧分压(PAO2)和氦-3表观扩散系数(ADC)，以及已建立的哮喘小鼠模型。我们将对通过成像和传统非成像技术获得的测量结果进行局部和整体的相关性研究，并尝试根据这些测量结果对健康和哮喘小鼠肺的状态进行量化。关键词：超极化氦-3MRI，肺功能成像，局部肺功能，局部肺结构，高精度啮齿动物呼吸机，局部氧分压，肺功能检测，表观弥散系数，区域通风，呼吸道重塑。公共卫生相关性：开发新的超极化氦-3磁共振成像技术，用于定量评估小鼠局部肺功能和结构。与常规肺功能测试相比，评估这些技术对哮喘小鼠模型诱导的气道重塑的敏感性，并对照组织学金标准标记物进行测量验证。

DESCRIPTION (provided by applicant): Quantitative regional assessment of lung function and structure has the potential to enhance early diagnosis and management of lung disease, and to provide more effective assessment of therapy. With this grant, we aim to develop regional quantitative techniques for measurement of lung function and structure in mice. We will utilize hyperpolarized helium-3 MRI technology to refine the apparatus and noninvasive technique for measuring lung ventilation, oxygenation and alveolar size in mice. The reproducibility and global validation of these imaging techniques will be conducted as part of this project. Furthermore we will systematically assess the sensitivity of each of these measurement techniques to presence and severity of a well-established inflammatory model of asthma in mice. In addition to studying sensitivity of these techniques to airway inflammatory response, we will study the correlation of these regional markers to gold standard measures of lung function and structure, namely pulmonary function testing and histopathology. The inherent heterogeneous characteristics of asthma suggests that imaging-based regional measurements of lung function and structure can potentially serve as more powerful tools in studying different aspects of this pulmonary disorder that may not be observable through global measurements of lung function. The ability to fully control ventilation parameters and repeat measurements with excellent reproducibility makes pulmonary imaging in small rodents very interesting. Such reproducibility is very hard to attain in larger animals. However, many of the currently existing hyperpolarized 3He MRI techniques - especially for measuring PAO2 - are not directly applicable in rodents and other small animals due to faster rate of physiological processes in these species, such as oxygen depletion rate, and physiological limitations on the length of breath-holds necessary for effective imaging. Thus the need for an established set of measurement tools to study regional aspect of rodent's pulmonary system, and specifically mice, is strongly felt in pulmonary research. Our group has recently developed methods that overcome these challenges, which by means of this grant, we aim to further refine. The central goal of this proposal is to develop, implement and refine hyperpolarized gas magnetic resonance imaging techniques to measure regional pulmonary ventilation (VA), partial pressure of oxygen (PAO2) and helium-3 apparent diffusion of coefficient (ADC) in the lungs of healthy mice, as well as in an established murine model of asthma. We will perform regional and overall correlation study between the measurements obtained from imaging and traditional non-imaging techniques, and attempt to quantitate the state of a the healthy and asthmatic mouse lung expressed in terms of these measurements. Keywords: Hyperpolarized Helium-3 MRI, Functional Pulmonary Imaging, Regional Lung Function, Regional Lung Structure, High Precision Rodent Ventilator, Regional Partial Pressure of Oxygen, Pulmonary Function Testing, Apparent Diffusion Coefficient, Regional Ventilation, Airway Remodeling. PUBLIC HEALTH RELEVANCE: To develop novel hyperpolarized helium-3 magnetic resonance imaging techniques for quantitative assessment of regional lung function and structure in mice. Assessment of the sensitivity of these techniques to airway remodeling induced by a murine model of asthma, compared to conventional pulmonary function tests, and validation of measurements against histological gold standard markers.