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)
Project #
Application #
Study Section
Special Emphasis Panel (ZHL1-CSR-R (M1))
Program Officer
Tigno, Xenia
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Brigham and Women's Hospital
United States
Zip Code
Nava, Rodrigo; Escalante-Ramírez, Boris; Cristóbal, Gabriel et al. (2014) Extended Gabor approach applied to classification of emphysematous patterns in computed tomography. Med Biol Eng Comput 52:393-403
Diaz, Alejandro A; Zhou, Linfu; Young, Tom P et al. (2014) Chest CT measures of muscle and adipose tissue in COPD: gender-based differences in content and in relationships with blood biomarkers. Acad Radiol 21:1255-61
Castaldi, Peter J; Cho, Michael H; San José Estépar, Raúl et al. (2014) Genome-wide association identifies regulatory Loci associated with distinct local histogram emphysema patterns. Am J Respir Crit Care Med 190:399-409
Wassermann, Demian; Ross, James; Washko, George et al. (2014) Deformable Registration of Feature-Endowed Point Sets Based on Tensor Fields. Proc IEEE Comput Soc Conf Comput Vis Pattern Recognit 2014:2729-2735
Kurugol, Sila; Washko, George R; Estepar, Raul San Jose (2014) RANKING AND CLASSIFICATION OF MONOTONIC EMPHYSEMA PATTERNS WITH A MULTI-CLASS HIERARCHICAL APPROACH. Proc IEEE Int Symp Biomed Imaging 2014:1031-1034
Ross, James C; Díaz, Alejandro A; Okajima, Yuka et al. (2014) AIRWAY LABELING USING A HIDDEN MARKOV TREE MODEL. Proc IEEE Int Symp Biomed Imaging 2014:554-558
Rudyanto, Rina D; Munoz-Barrutia, Arrate; Diaz, Alejandro A et al. (2013) MODELING AIRWAY PROBABILITY. Proc IEEE Int Symp Biomed Imaging :
Hunninghake, Gary M; Hatabu, Hiroto; Okajima, Yuka et al. (2013) MUC5B promoter polymorphism and interstitial lung abnormalities. N Engl J Med 368:2192-200
Cordova, Henry; San Jose Estepar, Raul; Rodriguez-D'Jesus, Antonio et al. (2013) Comparative study of NOTES alone versus NOTES guided by a new image registration system for navigation in the mediastinum: a study in a porcine model. Gastrointest Endosc 77:102-7
Estepar, Raul San Jose; Kinney, Gregory L; Black-Shinn, Jennifer L et al. (2013) Computed tomographic measures of pulmonary vascular morphology in smokers and their clinical implications. Am J Respir Crit Care Med 188:231-9

Showing the most recent 10 out of 18 publications