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.

Public Health Relevance

Chronic Obstructive Pulmonary Disease (COPD) affects up to 24 million people in the United States and is projected to be the 3rd leading cause of death worldwide by 2020. Unlike many other diseases, only rudimentary standards are available for describing the severity and the heterogeneity of COPD. This proposal assesses the validity of a new phenotype of airway disease, airway power, for the characterization of COPD based on a combination of X-ray attenuation and size of the airway wall measured from CT which can be used to define endpoints in clinical trials as well as to explore genome wide associations hence providing a benefit to the public health.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Mentored Quantitative Research Career Development Award (K25)
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Special Emphasis Panel (ZHL1-CSR-R (M1))
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Rothgeb, Ann E
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Brigham and Women's Hospital
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