Using MRI To Visualize Regional Therapy Response In Idiopathic Pulmonary Fibrosis

 描述(申请人提供)：特发性肺纤维化(IPF)患者的预后非常差，平均生存时间只有35.2个月。IPF目前影响着10万多名美国居民，其特征是肺血气屏障增厚和气体交换障碍。不幸的是，尽管为IPF开发治疗方法的努力正在加速，但由于无法充分描述该病的特征、其进展及其治疗反应，大多数临床试验都受到阻碍。现有的生物标志物要么太不敏感，要么太具侵入性，不能重复使用。我们打算通过引入一种全面的基于MRI的3D成像方法来解决这个问题，该方法不仅可以识别区域性疾病，还可以预测和观察区域性治疗反应。我们的长期目标是广泛应用非侵入性、高分辨率、定量的心肺功能所有方面的磁共振成像，以改变IPF的管理方式。我们的方法利用了结构和血流的1H磁共振成像的融合进展，以及超极化的129Xe磁共振通风和气体交换成像。本研究的目的是集成和优化这些结构和功能MRI方法，并使用它们来识别区域扩散限制，并比标准方法提前4倍预测和观察疗效。我们的中心假设是，结构、通风、灌注和气体交换的联合成像将提供识别疾病前沿的手段，在那里肺功能仍有可能恢复。这项拟议研究的基本原理是，使用全球指标检测治疗反应即使不是不可能，也是困难的，因此，需要非侵入性成像来可视化可恢复的区域。因此，拟议的研究与NIH任务中有关通过开发和加快生物医学技术的应用来改善健康的部分相关。在强大的初步数据指导下，我们的方法基于三个具体目标：1)在两个中心为IPF建立全面、定量的结构/功能MRI方案，2)结合Gd灌注和129Xe交换MRI识别区域性早期疾病，以及3)使用结构/功能MRI监测IPF的进展和治疗反应。完成这些目标将1)建立两个领先的中心，采用优化的IPF成像方案，2)建立可视化仍对治疗有反应的扩散损害区域的能力，3)在3个月内观察治疗反应，而不是1年内，以及4)如传统测试所看到的那样预测治疗后12个月的结果。建议的方法是创新的，因为它使用了一个全面的方案来衡量任何一种技术无法单独测量的东西，并利用两个中心的专业知识来加速开发和扩大这种罕见疾病的招募池。这项拟议的研究具有重要意义，因为它有可能开发关键的非侵入性功能成像生物标记物，使IPF试验能够以更快、更少的患者、更低的成本和更大的成功可能性进行。

 DESCRIPTION (provided by applicant): The prognosis for patients diagnosed with idiopathic pulmonary fibrosis (IPF) is very poor, with a mean survival time of only 35.2 months. IPF now affects more than 100,000 US residents and is characterized by thickening of the pulmonary blood-gas barrier and impaired gas exchange. Unfortunately, even as efforts to develop therapies for IPF accelerate, most clinical trials are stymied by the inability to adequately characterize the disease, its progression, and its therapeutic response. Existing biomarkers are either too insensitive or too invasive for repeat use. We intend to address this problem by introducing a comprehensive MRI-based 3D imaging approach to not only identify regional disease, but to predict and observe regional therapeutic response. Our long-term goal is to broadly deploy non-invasive, high-resolution, quantitative MR imaging of all aspects of cardiopulmonary function to change the way IPF is managed. Our approach exploits the converging progress in 1H MR imaging of structure and perfusion, with hyperpolarized 129Xe MR imaging of ventilation and gas exchange. The objective of this study is to integrate and optimize these structural and functional MRI approaches and use them to identify regional diffusion limitation, and predict and observe therapeutic response 4 times earlier than standard methods can. Our central hypothesis is that combined imaging of structure, ventilation, perfusion and gas exchange, will provide the means to identify the leading edge of disease, where recovery of lung function remains possible. The rationale for the proposed research is that therapeutic response is difficult if not impossible to detect using global metrics and thus, 3 non-invasive imaging is needed to visualize recoverable areas. 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, our approach is based on three Specific Aims: 1) Establish a comprehensive, quantitative structure/function MRI Protocol for IPF at two centers, 2) Identify regional early- stage disease by combining Gd perfusion and 129Xe exchange MRI, and 3) Use structure/function MRI to monitor progression and response to therapy in IPF. Completion of these aims will 1) set up 2-leading centers with an optimized protocol for imaging IPF, 2) establish the ability to visualize regions of diffusion impairment that can still respond to therapy, 3) observe therapeutic response within 3 months instead of 1 year, and 4) predict outcomes at 12 months post therapy as seen by conventional tests. The proposed approach is innovative because it uses a comprehensive protocol to measure what cannot be measured by any one technique in isolation, and exploits the expertise of 2 centers to accelerate development and expand the recruitment pool for this rare disease. The proposed research is significant because it has the potential to develop the key noninvasive functional imaging biomarkers that can enable IPF trials to be conducted faster, with fewer patients, at lower cost and with greater likelihood for success.