The earliest abnormalities associated with smoking are in the small airway epithelium (SAE), the basal, columnar, secretory and ciliated cells lining the airway lumen e 6th generations. The basal cells (BC) function as stem/progenitors that give rise to the differentiated epithelial cells that provide barrier function. Smoking disorders SAE differentiation, with BC hyperplasia and squamous metaplasia, more secretory cells, fewer and disordered ciliated cells, and altered leaky cell-cell junctions. The consequences are increased mucin production and inefficient mucociliary clearance, resulting in pathogen colonization and recruitment of inflammatory cells that further disorder lung architecture. Central to this proposal is the recognition that the SAE is the site initiating the pathogenesis of chronic obstructive pulmonary disease (COPD), and that BC play a critical role in the SAE disordering in COPD. While progress has been made in understanding the biology of the SAE and BC in health and disease, the focus has been on the contribution of single genes and pathways. Omics technology has led to the recognition that many genes are involved in the responses of the SAE to smoking and to COPD pathogenesis, and that the expression of these genes can be modified by the genome, epigenome, and miRNA. Our proposal is based on: (1) our ability to purify BC from brushed samples of the SAE;and (2) our analysis of the SAE transcriptome of a well characterized cohort of 161 subjects, including nonsmokers, healthy smokers and COPD smokers, all with demographic, lung function, HRCT chest imaging and genome-wide SNP arrays, with the SAE repeatedly sampled by bronchoscopy and brushing 4 times over 1 yr (0, 3, 6 and 12 months). Using de novo network recovery analysis of these samples, we identified 9 groups of connected hub genes (modules) comprised of 273 hub genes and 10 significant pathways that differentiate COPD from smoking. We propose to build on this network to analyze the influence of genetic, epigenetic and miRNA expression variability on key transcriptome modules, hubs and connectivities that de- fine how SAE biology becomes disordered with the development of COPD.
Aim 1. To assess the effects of variability of genome, epigenome (methylation) and miRNA expression on the SAE transcriptome COPD-differentiated hubs and connections.
Aim 2. To examine the hypothesis that the modules, hubs and connectivities that characterize the SAE COPD transcriptome are dominated by BC biology.
Aim 3. To test the hypothesis that modification of the SAE hubs that differentiate COPD will have significant consequences on the connected genes that characterize the disordered SAE COPD-differentiated transcriptome. Our deliverable will be the identification of potential hub drug targets to reverse and/or prevent the disordered biology that characterizes the COPD SAE.
Chronic obstructive pulmonary disease (COPD), a disease caused by cigarette smoking, starts in the small airway epithelium (SAE), the cells lining the airways e 6th generations. Using a well characterized cohort and data set of nonsmokers, healthy smokers and COPD smokers relating to the biology of the SAE in health and disease, we propose to build a computational, systems level model of the biology of the SAE as it becomes disordered with the development of COPD, with a focus on identifying key transcriptional hubs that can serve as targets for drugs to prevent and treat COPD.
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