MicroRNA profiling of chronic lung disease for the Lung Genomics Research Consortium
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ABSTRACT: These subjects were diagnosed as being controls or having interstitial lung disease (ILD) or chronic obstructive pulmonary disease (COPD) as determined by clinical history, CT scan, and surgical pathology. There was no intervention, these are cross-sectional data. All samples are from the Lung Tissue Research Consortium (LTRC) and are indexed by their LTRC tissue label. These are 319 total subjects, 183 have ILD and 136 have COPD, who went for surgery for the investigation of a nodule and have no chronic lung disease by CT or pathology. Each sample is total RNA extracted from flash frozen human whole lung homogenate. Between the two platforms were analyzed. Samples are titled by source (LT=LTRC), 6-digit tissue label, lobe of extraction, and major disease state.
Project description:These subjects were diagnosed as being controls or having interstitial lung disease (ILD) or chronic obstructive pulmonary disease (COPD) as determined by clinical history, CT scan, and surgical pathology. There was no intervention, these are cross-sectional data. All samples are from the Lung Tissue Research Consortium (LTRC) and are indexed by their LTRC tissue label.
Project description:Microarray data from total RNA extracted from whole lung homogenate from subjects undergoing thoracic surgery. These subjects were diagnosed as being controls or having interstitial lung disease or COPD as determined by clinical history, CT scan, and surgical pathology. There was no intervention, these are cross-sectional data. All samples are from the Lung Tissue Research Consorium (LTRC and are indexed by their LTRC tissue label). These are 582 total subjects, 254 have interstitial lung disease, 220 have COPD, and 108 are controls, who went for surgery for the investigation of a nodule and have no chronic lung disease by CT or pathology. Due to the number of samples, multipe batches of arrays were necessary, so 10% of the arrays were picked at random to have replicates throughout each batch to account for possible batch effects. The feature extracted data was normalized using a pairwise cyclic loess approach, and the probes were collapsed to one probe per gene by selecting the probe with the highest average signal. Each sample is total RNA extracted from flash frozen human whole lung homogenate. Between the two platforms were analyzed. Samples are titled by source (LT=LTRC), 6-digit tissue label, lobe of extraction, and major disease state)
Project description:Microarray data from total RNA extracted from whole lung homogenate from subjects undergoing thoracic surgery. These subjects were diagnosed as being controls or having interstitial lung disease or COPD as determined by clinical history, CT scan, and surgical pathology. There was no intervention, these are cross-sectional data. All samples are from the Lung Tissue Research Consorium (LTRC and are indexed by their LTRC tissue label).
Project description:Chronic obstructive pulmonary disease (COPD) and interstitial lung disease (ILD) are clinically and molecularly heterogeneous diseases. We utilized clustering and integrative network analyses to elucidate roles for microRNAs (miRNAs) and miRNA isoforms (isomiRs) in COPD and ILD pathogenesis. Short RNA sequencing was performed on 351 lung tissue samples of COPD (n=145), ILD (n=144) and controls (n=64). Five distinct subclusters of samples were identified including 1 COPD-predominant cluster and 2 ILD-predominant clusters which associated with different clinical measurements of disease severity. Utilizing 262 samples with gene expression and SNP microarrays, we built disease-specific genetic and expression networks to predict key miRNA regulators of gene expression. Members of miR-449/34 family, known to promote airway differentiation by repressing the Notch pathway, were among the top connected miRNAs in both COPD and ILD networks. Genes associated with miR-449/34 members in the disease networks were enriched among genes that increase in expression with airway differentiation at an air-liquid interface. A highly expressed isomiR containing a novel seed sequence was identified at the miR-34c-5p locus. 47% of the anticorrelated predicted targets for this isomiR were distinct from the canonical seed sequence for miR-34c-5p. Overexpression of the canonical miR-34c-5p and the miR-34c-5p isomiR with an alternative seed sequence down-regulated NOTCH1 and NOTCH4. However, only overexpression of the isomiR down-regulated genes involved in Ras signaling such as CRKL and GRB2. Overall, these findings elucidate molecular heterogeneity inherent across COPD and ILD patients and further suggest roles for miR-34c in regulating disease-associated gene-expression.
Project description:There is a pressing need to identify early biomarkers of lung involvement in systemic sclerosis (SSc) to start as soon as possible antifibrotic therapy. We aimed to identify extracellular vesicle-derived microRNAs (EV-miRNAs) that are differentially expressed between SSc patients with and without interstitial lung disease (ILD) and explore their diagnostic value. Small EVs derived from plasma were isolated from 20 well-characterised SSc patients with ILD (SSc-ILD, n=10), without ILD (SSc-no ILD, n=10) and 10 matched healthy subjects (HS). Small RNA sequencing was used to identify sEV-miRNAs associated to SSc-ILD.
Project description:We identified eighty two skin transcripts significantly correlated with the severity of interstitial lung disease (ILD) in systemic sclerosis. These genes separated patients with more sever ILD in unsupervised hierarchical clustering. Pathway analysis revealed pathways involved in extravasation and adhesion of inflammatory cells to endothelium. Skin biopsy samples from 59 patients enrolled in the GENISOS cohort or an open label imatinib study were examined by global gene expression studies.
Project description:70 miRNAs and 2667 mRNAs were differentially expressed between lung tissue from subjects with COPD and smokers without COPD. miRNA and mRNA expression profiles enriched for biological pathways that may be relevant to the pathogenesis of COPD including the transforming growth factor b, Wnt and focal adhesion pathways. miR-223 and miR-1274a were the most affected miRNAs in subjects with COPD compared with smokers without obstruction. miR-15b was increased in COPD samples compared with smokers without obstruction and localised to both areas of emphysema and fibrosis. miR-15b was differentially expressed within GOLD classes of COPD. Expression of SMAD7, which was validated as a target for miR-15b, was decreased in bronchial epithelial cells in COPD. Lung tissue from smokers with no evidence of obstructive lung disease and smokers with COPD was examined for miRNA and mRNA expression followed by validation. We then examined both miRNA and mRNA expression to enrich for relevant biological pathways
Project description:Chronic obstructive pulmonary disease (COPD) is an inflammatory lung disease with complex pathological features and largely unknown etiologies. Identification and validation of biomarkers for this disease could facilitate earlier diagnosis, appreciation of disease subtypes and/or determination of response to therapeutic intervention. To identify gene expression markers for COPD, we performed genome-wide expression profiling of lung tissue from 56 subjects using the Affymetrix U133 Plus 2.0 array. Lung function measurements from these subjects ranged from normal, un-obstructed to severely obstructed. Analysis of differential expression between cases (FEV1<70%, FEV1/FVC<0.7) and controls (FEV1>80%, FEV1/FVC>0.7) identified a set of 65 probe sets representing discrete markers associated with COPD. Correlation of gene expression with quantitative measures of airflow obstruction (FEV1 or FEV1/FVC) identified a set of 220 probe sets. A total of 31 probe sets were identified that showed evidence of significant correlation with quantitative traits and differential expression between cases and controls. Experiment Overall Design: We assessed genome-wide expression patterns in lung tissue specimens derived from 56 subjects. These subjects were undergoing lobectomy for removal of a suspected tumor, and tissue for our studies was derived from histologically normal tissue distant from the tumor margin. Subjects underwent routine spirometry prior to surgery. Low values for both FEV1 and FEV1/FVC are characteristic features of COPD and associated with the severity of disease. For our studies, Cases (n=15) were defined as subjects with FEV1<70% and FEV1/FVC<0.7 and Controls (n=18) as subjects with FEV1>80% and FEV1/FVC>0.7. A majority of the subjects were diagnosed with adenocarcinoma (n=26) or squamous cell carcinoma (n=19), while other tumor types or benign lesions were found in the remaining subjects (n=11).
Project description:Little is known about the lung microbiome dynamics and host-microbiome interactions in relation to chronic obstructive pulmonary disease (COPD) exacerbations and in patient subgroups based on smoking status and disease severity. Here we performed a 16S ribosomal RNA survey on sputum microbiome from 16 healthy and 43 COPD subjects. For COPD subjects, a longitudinal sampling was performed from stable state to exacerbations, at two and six weeks post-exacerbations and at six months from first stable visit. Host sputum transcriptome were characterized for a subset of COPD patient samples.