Project description:Towards individual radiosensitivity / late radiation injury: Dose estimates provide only a general idea of the average radiation injury expected across a population. Predictors of individual radiation injury response and outcome will be even more useful. Building on our successful studies of blood-based transcriptomic predictors for individualized radiation-induced ARS mortality, we will assess the utility of gene expression biomarkers for the individualized prediction of later mortality from lung injury. We will develop signatures of injury and recovery, and use mouse models to investigate the impact of inflammatory pathways on our biodosimetric signatures. We then performed gene expression profiling analysis using data obtained from RNA-seq of 4 different cells at two time points.
Project description:Lung donation after cardiac death (DCD), in contrast to donation after brain death (DBD), is a promising and increasingly common method to help relieve the shortage of donor organs. However, the pathogenetic consequences of retrieved lungs after DCD vs. DBD have not been clarified. We aimed to study the differential gene expression profiles in lungs of DCD and DBD patients. DCD patients were matched with DBD lung transplant cases from a prospectively maintained database. The number of tissue samples included in this study was 6 pre- and 5 post-transplant in DCD and 12 pre- and 12 post-transplant in DBD for a total number of 35 lung tissue samples.
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:The mechanisms and molecular pathways underlying interstitial lung diseases (ILDs) are poorly understood. Systems biology approaches were used to identify perturbed networks in these disease states to gain a better understanding of the underlying mechanisms of disease. Through profiling genes and miRNAs, we found subsets of genes and miRNAs that distinguish different disease stages, ILDs from controls, and idiopathic pulmonary fibrosis (IPF) from non-specific interstitial pneumonitis (NSIP). Traditional pathway analysis revealed several disease-associated modules involving genes from the TGF-beta, Wnt, focal adhesion and smooth muscle actin pathways that may be involved in advancing fibrosis. A comprehensively integrative approach was used to construct a global gene regulatory network based on the perturbation of key regulatory elements, transcriptional factors and miRNAs. The data also demonstrated that several subnetworks were significantly associated with key molecules involved in the diseases. We present a broad overview of the disease at a molecular level and discuss several possibly key regulatory molecular circuits that could play central roles in facilitating the progression of ILDs. Lung tissue samples from 23 patients with IPF or related disorders were obtained from the Lung Tissue Research Consortium (www.ltrcpublic.org). 11 samples came from patients who had been diagnosed with usual interstitial pneumonia/ idiopathic pulmonary fibrosis (UIP/IPF), 5 samples came from patients with non-specific interstitial pneumonia (NSIP), the remaining from patients with uncharacterized fibrosis and from patients with other ILD variants. B. Biopsies from uninvolved lung tissue from lung cancer patients (5 samples) and from one lung transplant patient were used as controls for comparison with the ILD samples.
Project description:Chronic obstructive pulmonary disease (COPD) is an independent risk factor for lung cancer, suggesting that COPD stroma favors cancer initiation. Therefore, we used proteomics and polysome-profiling to identify gene expression programs that distinguish stroma of patients harboring lung cancer from those that do not, with varied COPD severities. This profiling unveiled distinct COPD-dependent cancer-associated gene expression programs predominantly manifesting as alterations in mRNA translation. Mechanistically, such programs are downstream of the mammalian target of rapamycin pathway in mild COPD and pathological extracellular matrix in more severe COPD; and both programs parallel activation of distinct pro-cancer fibroblast-derived secretomes. Therefore, depending upon COPD severity, the lung stroma can exist in two states favoring cancer initiation, which likely result in distinct disease entities.