Chronic Obstructive Pulmonary Disease (COPD) is the fifth leading cause of death in the United States. COPD is a highly heterogeneous disease, and patients with COPD experience varying degrees of respiratory findings (lung function decline, chronic bronchitis, and emphysema). However, the molecular changes underlying this heterogeneity are not well understood. For my dissertation research I used bronchial airway gene expression to develop a signature of lung function decline, evaluate a molecule for potential anti-COPD properties, and develop a gene expression-based classification of COPD subtypes.
Genome-wide gene expression generated from bronchial epithelial brushings of ever smokers with and without COPD were used to identify differences in gene expression associated with the rate of subsequent lung function decline. I validated this lung function decline signature in an independent set of COPD patients and determined that this signature may be driven by changes in the activity of the transcription factor XBP1. I next identified gene expression changes in human derived bronchial epithelial cells (HBECS) when exposed to a potential novel anti-COPD compound. I performed an in silico analysis to determine if these gene expression changes were related to COPD-associated gene expression differences observed in independent datasets of COPD patients. Lastly, I performed unbiased gene expression clustering on bronchial brushings to identify novel molecular COPD subtypes. I then examined these gene expression changes in independent datasets of COPD.
Together, these works may lead to better understanding and treatment of COPD. The signature of lung function decline could be used as an intermediary endpoint in studies evaluating COPD therapies, or for patient stratification. Characterizing the relationship between the gene expression changes associated with COPD and those induced by the novel anti-COPD compound helps inform choices around its development as a potential medication. Lastly, the molecular subtypes of COPD may lead to a better understanding of molecular heterogeneity in the pathogenesis of COPD and ultimately more patient-specific treatments that are targeted to these molecular differences. / 2023-05-25T00:00:00Z
| Identifer | oai:union.ndltd.org:bu.edu/oai:open.bu.edu:2144/42637 |
| Date | 26 May 2021 |
| Creators | Becker, Elizabeth J. |
| Contributors | Steiling, Katrina, Spira, Avrum |
| Source Sets | Boston University |
| Language | en_US |
| Detected Language | English |
| Type | Thesis/Dissertation |
| Rights | Attribution-NonCommercial 4.0 International, http://creativecommons.org/licenses/by-nc/4.0/ |
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