Filters
Technology
Platform
GSE21071
Sus scrofa
40 Downloadable Samples
Affymetrix Porcine Genome Array (porcine)
Description
Lung disease causes most of the morbidity and mortality in cystic fibrosis (CF). However, understanding its pathogenesis has been hindered by lack of an animal model with characteristic features of CF. To overcome this problem, we recently generated pigs with targeted CFTR genes. We now report that within months of birth, CF pigs spontaneously develop hallmark features of CF lung disease including airway inflammation, remodeling, mucus accumulation, and infection. Their lungs contained multiple bacterial species, suggesting an equal opportunity host defense defect. In humans, the temporal and/or causal relationships between inflammation and infection have remained uncertain. To investigate these processes, we studied newborn pigs. Their lungs showed no inflammation, but were less often sterile than controls. Moreover, after intrapulmonary bacterial challenge, CF pigs failed to eradicate bacteria as effectively as wild- type pigs. These results suggest that impaired bacterial elimination is the pathogenic event that initiates a cascade of inflammation and pathology in CF lungs. Finding that CF pigs have a bacterial host defense defect within hours of birth provides an exciting opportunity to further investigate pathogenesis and to test therapeutic and preventive strategies before secondary consequences develop.
Publication Title
Cystic fibrosis pigs develop lung disease and exhibit defective bacterial eradication at birth.
Sample Metadata Fields
Specimen part
View Samples- Homo sapiens
- 12 Downloadable Samples
- Affymetrix Human Gene 1.0 ST Array (hugene10st)
Description
Production of functional proteins requires multiple steps including gene transcription and post-translational processing. MicroRNAs (miRNA) can regulate individual stages of these processes. Despite the importance of the cystic fibrosis transmembrane conductance regulator (CFTR) channel for epithelial anion transport, how its expression is regulated remains uncertain. We discovered that microRNA-138 regulates CFTR expression through its interactions with the transcriptional regulatory protein SIN3A. Treating airway epithelia with a miR-138 mimic increased CFTR mRNA and also enhanced CFTR abundance and transepithelial Cl- permeability independently of elevated mRNA levels. A miR-138 anti-miR had the opposite effects. Importantly, miR-138 altered the expression of many genes encoding proteins that associate with CFTR and may influence its biosynthesis. The most common CFTR mutation, F508, causes protein misfolding, degradation, and cystic fibrosis. Remarkably, manipulating the miR-138 regulatory network also improved biosynthesis of CFTR-F508 and restored Cl- transport to cystic fibrosis airway epithelia. This novel miRNA-regulated network directs gene expression from the chromosome to the cell membrane, indicating that an individual miRNA can control a cellular process broader than previously recognized. This discovery also provides new therapeutic avenues for restoring CFTR function to cells affected by the most common cystic fibrosis mutation.
Publication Title
A microRNA network regulates expression and biosynthesis of wild-type and DeltaF508 mutant cystic fibrosis transmembrane conductance regulator.
Sample Metadata Fields
Specimen part, Cell line
View Samples- Sus scrofa
- 11 Downloadable Samples
- Affymetrix Porcine Genome Array (porcine)
Description
Cystic fibrosis (CF) is a life-shortening disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Although bacterial lung infection and the resulting inflammation cause most of the morbidity and mortality, how loss of CFTR first disrupts airway host defense has remained uncertain. We asked what abnormality impairs elimination when a bacterium lands on the pristine surface of a newborn CF airway? To investigate this defect, we interrogated the viability of individual bacteria immobilized on solid grids and placed on the airway surface. As a model we studied CF pigs, which spontaneously develop hallmark features of CF lung disease. At birth, their lungs lack infection and inflammation, but have a reduced ability to eradicate bacteria. Here we show that in newborn wild-type pigs, the thin layer of airway surface liquid (ASL) rapidly killed bacteria in vivo, when removed from the lung, and in primary epithelial cultures. Lack of CFTR reduced bacterial killing. We found that ASL pH was more acidic in CF, and reducing pH inhibited the antimicrobial activity of ASL. Reducing ASL pH diminished bacterial killing in wild-type pigs, and increasing ASL pH rescued killing in CF pigs. These results directly link the initial host defense defect to loss of CFTR, an anion channel that facilitates HCO3- transport. Without CFTR, airway epithelial HCO3- secretion is defective, ASL pH falls and inhibits antimicrobial function, and thereby impairs killing of bacteria that enter the newborn lung. These findings suggest that increasing ASL pH might prevent the initial infection in patients with CF and that assaying ASL pH or bacterial killing could report on the benefit of therapeutic interventions.
Publication Title
Reduced airway surface pH impairs bacterial killing in the porcine cystic fibrosis lung.
Sample Metadata Fields
Specimen part
View Samples- Homo sapiens
- 6 Downloadable Samples
- Affymetrix Human Exon 1.0 ST Array [probe set (exon) version (huex10st)
Description
Differential gene expression in preimplantation embryos has been documented, but few focused studies have been done to compare differential expression in human embryos after embryonic genome activation and specifically how they relate to blastocyst development. We hypothesized that blastocyst stage embryos would differentially express genes in pathways important in cell division, mobilization, and processes important in embryo implantation including endometrial apposition, adhesion, and invasion. We analyzed gene expression in 6 preimplantation human embryos.
Publication Title
Differentially expressed genes in preimplantation human embryos: potential candidate genes for blastocyst formation and implantation.
Sample Metadata Fields
Specimen part
View Samples- Mus musculus
- 82 Downloadable Samples
- Affymetrix Mouse Genome 430A 2.0 Array (mouse430a2)
Description
We extracted nascent plasma cell tumor (PCT) cells from within inflammatory granulomas (OG) isolated from intraperitoneal pristane-injected BALB/c.iMyc E mice at five different time points during tumor progression. We used laser capture micro-dissection to collect incipient PCT cells and analyzed their global gene expression on Affymetrix Mouse Genome 430A microarrays. Two independent studies were performed with different sets of mice
Publication Title
Global gene expression profiling in mouse plasma cell tumor precursor and bystander cells reveals potential intervention targets for plasma cell neoplasia.
Sample Metadata Fields
Specimen part
View Samples- Mus musculus
- 48 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
Our goal was to identify gene expression patterns that correlated with prevention of autoimmune alopecia in C3H/HeJ mice following alopecic graft transplantation
Publication Title
Alopecia areata is driven by cytotoxic T lymphocytes and is reversed by JAK inhibition.
Sample Metadata Fields
Specimen part, Treatment
View Samples- Homo sapiens
- 43 Downloadable Samples
- Affymetrix Human Exon 1.0 ST Array [transcript (gene) version (huex10st)
Description
The objective of the overall study was to determine the effects of oral vitamin D supplementation on alveolar macrophages from human subjects. In this substudy, subjects treated with vitamin D (intervention group) in paired analysis had small, but significant effects on immune-related differential gene expression pre versus post supplementation.
Publication Title
Effects of vitamin D supplementation on alveolar macrophage gene expression: preliminary results of a randomized, controlled trial.
Sample Metadata Fields
Specimen part, Treatment, Subject
View Samples- Homo sapiens
- 32 Downloadable Samples
- Illumina HumanHT-12 V4.0 expression beadchip
Description
There is a critical need in cancer therapeutics to identify targeted therapies that will improve outcomes and decrease toxicities compared to conventional, cytotoxic chemotherapy. Ewing sarcoma is a highly aggressive bone and soft tissue cancer that is caused by the EWS-FLI1 fusion protein. Although EWS-FLI1 is specific for cancer cells, and required for tumorigenesis, directly targeting this transcription factor has proven challenging. Consequently, targeting unique dependencies or key downstream mediators of EWS-FLI1 represent important alternative strategies. We used gene expression data derived from a genetically defined model of Ewing sarcoma to interrogate the Connectivity Map and identify a class of drugs, iron chelators, that downregulate a significant number of EWS-FLI1 target genes. We then identified ribonucleotide reductase M2 (RRM2), the iron-dependent subunit of ribonucleotide reductase (RNR), as one mediator of iron chelator toxicity in Ewing sarcoma cells. Inhibition of RNR in Ewing sarcoma cells led to apoptosis and cell death in vitro and attenuated tumor growth in vivo in a xenograft model. Additionally, we discovered that the sensitivity of Ewing sarcoma cells to inhibition or suppression of RNR is mediated, in part, by high levels of SLFN11, a protein that sensitizes cells to DNA damage. This work demonstrates a unique dependency of Ewing sarcoma cells on RNR and supports further exploration of clinically used inhibitors of RNR as a therapeutic approach in treating this cancer.
Publication Title
Gene expression signature based screening identifies ribonucleotide reductase as a candidate therapeutic target in Ewing sarcoma.
Sample Metadata Fields
Specimen part, Cell line, Treatment
View Samples- Mus musculus
- 33 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
Reversal of Alopecia Areata Following Treatment With the JAK1/2 Inhibitor Baricitinib.
Sample Metadata Fields
Specimen part, Treatment, Time
View Samples- Mus musculus
- 31 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
Our goal was to identify gene expression patterns that correlated with treatment of established autoimmune alopecia in C3H/HeJ mice following alopecic graft transplantation
Publication Title
Alopecia areata is driven by cytotoxic T lymphocytes and is reversed by JAK inhibition.
Sample Metadata Fields
Specimen part, Treatment
View Samples