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

描述（由申请人提供）：在慢性阻塞性肺疾病（COPD）患者中，气道重塑在气道功能中起着重要作用。这种重塑是由改变气道形态和组成的炎症和纤维化过程驱动的。该建议验证了计算机断层扫描（CT）可用于评估与气道重塑相关的气道壁组织病理学变化的假设，并且这些变化可用于定义新的表型以建立候选基因的全基因组关联。该过程的壁炎和纤维化特征可能改变气道大小和组织密度，以至于在CT扫描上可以检测到。该提案的主要目的是验证和应用COPD的一种新的表型，即气道功率，基于与该疾病的组织病理学成分相关的气道壁x射线衰减。这种新的表型具有可以在CT中精确计算气道理想化模型的特性。具体来说，我们将使用计算机化和人工模型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气道组织阻塞；具体来说，是组织显微数字图像、微焦x射线计算机断层扫描（microfocal x -ray computed tomography, microCT）和标准临床CT。组织样本将用微ct技术扫描，以提供放射学基线，可用于将形态学测量和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。相同的组织样本将在COPD标准临床护理中使用的标准高分辨率CT （HRCT）扫描仪上进行扫描，并将在微CT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，将用于建立候选基因的全基因组关联，使用来自COPDGene的3000个受试者CT扫描。这项研究是San Josi Estipar博士五年职业发展计划的核心，在三位杰出研究人员的指导下，以及四位在肺生理学、遗传流行病学和图像分析领域具有专业知识的委员会成员的建议下。拟议的职业规划将这些领域的教学和实践培训结合在哈佛医学院、哈佛公共卫生学院和布里格姆妇女医院独特的学术和研究环境中。该职业规划将使San Josi Estipar博士成为一名成熟的独立定量研究科学家，拥有开发基于图像的定量方法的专业知识，从而能够进行COPD和相关肺部疾病的临床和遗传研究。

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.