CT-based Phenotype for Airway Remodeling in COPD based on Airway Wall Density

描述(申请人提供)：在慢性阻塞性肺疾病(COPD)中，气道重塑在呼吸道功能中起着基础性的作用。这种重塑是由炎症和纤维化过程驱动的，改变了呼吸道的形态和组成。这一建议验证了这样一种假设，即计算机断层扫描(CT)可用于评估与气道重塑相关的气道壁的组织病理学变化，以及这些变化可用于定义新的表型以在候选基因中建立全基因组关联。这一过程的附壁炎症和纤维化特征可能会改变呼吸道的大小和组织密度，以至于在CT扫描中可以检测到。这项建议的广泛目标是验证和应用一种新的COPD表型，即基于与疾病组织病理学成分相关的气道壁X射线衰减的气道动力。这种新的表型具有可以在CT中相对于理想的呼吸道模型进行准确计算的特性。具体地说，我们将使用计算机化的和人造的幻影来验证这种新的表型。然后，我们提出了一项体外验证研究，通过多种方式评估中央呼吸道组织块；具体地说，组织学显微镜数字图像、微焦点X射线计算机体层摄影(MicroCT)和标准临床CT。组织样本将使用MicroCT技术进行扫描，以提供可用于将形态测量和X射线衰减值与病理学家评估的组织病理学成分进行比较的放射基线。相同的组织样本将在标准的COPD临床护理中使用的标准高分辨率CT(HRCT)扫描仪中进行扫描，并将与在MicroCT水平和组织学水平上获得的测量结果建立相关性。此外，这种新的表型以及壁厚表型将被用于通过COPDgene的3000例受试者CT扫描在候选基因中建立全基因组范围的关联。这项研究是San Josi Estipar博士五年职业发展计划的核心，在三项杰出研究的指导下，以及在以下领域拥有专业知识的四名委员会成员的建议下：肺生理学、遗传流行病学和图像分析。拟议的职业计划在哈佛医学院、哈佛公共卫生学院以及布里格姆和妇女医院独特的学术和研究环境下，将这些领域的授课和实践培训结合在一起。该职业生涯规划将把San Josi Estipar博士培养成一名成熟的独立定量研究科学家，具有开发基于图像的定量方法的专业知识，从而能够对慢性阻塞性肺病和相关肺部疾病进行临床和遗传学研究。

DESCRIPTION (provided by applicant): Airway remodeling plays a fundamental role in the function of the airways in Chronic Obstructive Pulmonary Diseases (COPD). This remodeling is driven by an inflammatory and fibrotic process that changes both the airway morphology and composition. This proposal tests the hypothesis that Computed Tomography (CT) may be used to evaluate the histopathological changes in the airway walls associated with airway remodeling and that that those changes can be used to define a new phenotype to establish genome-wide associations in candidate genes. The mural inflammation and fibrosis characteristic of this process may change airway size and tissue density to such a degree that it is detectable on CT scans. The broad objective of this proposal is to validate and apply a new phenotype for COPD, airway power, based on X-ray attenuation of the airway wall that correlates with the histopathology components of the disease. This new phenotype has the property that can be accurately computed in CT with respect to an idealized model of an airway. Specifically, we will validate this new phenotype using computerized and artificial phantoms. Then, we propose an ex-vivo validation study that assesses central airway tissue blocks by means of multiple modalities; specifically, histology microscopy digital images, microfocal X-ray-computed tomography (microCT) and standard clinical CT. Tissue samples will be scanned with microCT technology to provide a radiological baseline that can be used to compare morphology measurements and X-ray attenuation values with histopathology components assessed by a pathologist. The same tissue samples will be scanned in standard High Resolution CT (HRCT) scanners used in standard clinical care of COPD and correlations will be established with the measurements obtained at the microCT level and the histology level. In addition, this new phenotype, as well as wall thickness phenotypes, will be used to establish genome-wide associations in candidate genes using 3000 subject CT scans from COPDGene. This research is the core of a five year career development plan for Dr. San Josi Estipar under the mentorship of three outstanding researches and the advice of four committee members with expertise in the following areas: lung physiology, genetic epidemiology and image analysis. The proposed career plan combines didactic and practical training in these areas within the unique academic and research environment of Harvard Medical School, Harvard School of Public Health and Brigham and Women's Hospital. The career plan will foster Dr. San Josi Estipar into an established independent quantitative research scientist with the expertise to develop image-based quantitative approaches to enable clinical and genetic studies in COPD and related lung diseases.