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SRP033407
Mus musculus
20 Downloadable Samples
Illumina HiSeq 1000
Description
Pulmonary fibrosis is often triggered by an epithelial injury resulting in the formation of fibrotic lesions in the lung, which progress to impair gas exchange and ultimately cause death. Recent clinical trials using drugs that target either inflammation or a specific molecule have failed, suggesting that multiple pathways and cellular processes need to be attenuated for effective reversal of established and progressive fibrosis. Although activation of MAPK and PI3K pathways have been detected in human fibrotic lung samples, the therapeutic benefits of in vivo modulation of the MAPK and PI3K pathways in combination are unknown. Overexpression of TGFa in the lung epithelium of transgenic mice results in the formation of fibrotic lesions similar to those found in human pulmonary fibrosis, and previous work from our group shows that inhibitors of either the MAPK or PI3K pathway can alter the progression of fibrosis. In this study, we sought to determine whether simultaneous inhibition of the MAPK and PI3K signaling pathways is a more effective therapeutic strategy for established and progressive pulmonary fibrosis. Our results showed that inhibiting both pathways had additive effects compared to inhibiting either pathway alone in reducing fibrotic burden, including reducing lung weight, pleural thickness, and total collagen in the lungs of TGFa mice. This study demonstrates that inhibiting MEK and PI3K in combination abolishes proliferative gene changes associated with fibrosis and myfibroblast accumulation and thus may serve as a therapeutic option in the treatment of human fibrotic lung disease where these pathways play a role. Overall design: mRNA profiles of CCSP/TGFalpha mice treated with vehicle, ARRY, PX-866, ARRY/PX-866
Publication Title
Dual targeting of MEK and PI3K pathways attenuates established and progressive pulmonary fibrosis.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 15 Downloadable Samples
- Illumina HiSeq 2000
Description
Insulin-producing beta cells become dedifferentiated during diabetes progression. An impaired ability to select substrates for oxidative phosphorylation, or metabolic inflexibility, sets the stage for progression from beta cell dysfunction to beta cell dedifferentiation. In this study, we sought to isolate and functionally characterize failing beta cells, as a preliminary step to identify pathways to reverse dedifferentiation. Using various experimental models of diabetes, we found a striking enrichment in the expression of aldehyde dehydrogenase 1 isoform A3 (ALDH+) as beta cells become dedifferentiated. Flow-sorted ALDH+ islet cells demonstrate impaired glucose-induced insulin secretion, are depleted of Foxo1 and MafA, and include a Neurogenin3-positive subset. RNA sequencing analysis demonstrates that ALDH+ cells are characterized by: (i) impaired oxidative phosphorylation and mitochondrial complex I, IV, and V; (ii) activated RICTOR; and (iii) progenitor cell markers. We propose that impaired mitochondrial function marks the progression from metabolic inflexibility to dedifferentiation in the natural history of beta cell failure. Overall design: RNA-Sequencing analysis of 2 different cell types in 2 different genotype categories.
Publication Title
Aldehyde dehydrogenase 1a3 defines a subset of failing pancreatic β cells in diabetic mice.
Sample Metadata Fields
Specimen part, Subject
View Samples- Mus musculus
- 4 Downloadable Samples
- Illumina HiSeq 2000
Description
Pancreatic beta-cell dysfunction contributes to onset and progression of type 2 diabetes. In this state beta-cells become metabolically inflexible, losing the ability to select between carbohydrates and lipids as substrates for mitochondrial oxidation. These changes lead to beta-cell dedifferentiation. We have proposed that FoxO proteins are activated through deacetylation-dependent nuclear translocation to forestall the progression of these abnormalities. However, how deacetylated FoxO exert their actions remains unclear. To address this question, we analyzed islet function in mice homozygous for knock-in alleles encoding deacetylated FoxO1 (6KR). Islets expressing 6KR mutant FoxO1 have enhanced insulin secretion in vivo and ex vivo, and decreased fatty acid oxidation ex vivo. Remarkably, the gene expression signature associated with FoxO1 deacetylation differs from wild-type by only ~2% of the > 4,000 genes regulated in response to re-feeding. But this narrow swath includes key genes required for beta-cell identity, lipid metabolism, and mitochondrial fatty acid and solute transport. The data support the notion that deacetylated FoxO1 protects beta-cell function by limiting mitochondrial lipid utilization, and raise the possibility that inhibition of fatty acid oxidation in ß-cells is beneficial to diabetes treatment. Overall design: Examined 2 different feeding state and 2 different genotypes
Publication Title
FoxO1 Deacetylation Decreases Fatty Acid Oxidation in β-Cells and Sustains Insulin Secretion in Diabetes.
Sample Metadata Fields
Cell line, Subject
View Samples- Homo sapiens
- 18 Downloadable Samples
Affymetrix Human Genome U133A Array (hgu133a)
Description
BACKGROUND: Mammalian microRNAs (miR) regulate the expression of genes relevant for the development of adaptive and innate immunity against cancer. Since T cell dysfunction has previously been reported in patients with renal cell carcinoma (RCC; clear cell type), we aimed to analyse these immune cells for genetic and protein differences when compared to normal donor T cells freshly after isolation and 35 days after in vitro stimulation (IVS) with HLA-matched RCC tumor cells.
Publication Title
miR-29b and miR-198 overexpression in CD8+ T cells of renal cell carcinoma patients down-modulates JAK3 and MCL-1 leading to immune dysfunction.
Sample Metadata Fields
Sex, Age, Specimen part, Disease, Subject, Time
View Samples- Mus musculus
- 6 Downloadable Samples
- Illumina HiSeq 2500
Description
Insulin action in adipocytes affects whole-body insulin sensitivity. Studies of adipose-specific Glut4 knockout mice have established that adipose Glut4 contributes to the control of systemic glucose homeostasis. Presumably, this reflects a role for Glut4-mediated glucose transport in the regulation of secreted adipokines. In cultured 3T3-L1 adipocytes, Rab10 GTPase is required for insulin-stimulated translocation of Glut4 (Sano et al., 2007). The physiological importance of adipose Rab10 and the significance of its role in the control of Glut4 vesicle trafficking in vivo are unknown. Here we report that adipocytes from adipose-specific Rab10 knockout mice have a ~50% reduction in glucose uptake and Glut4 translocation to the cell surface in response to insulin, demonstrating a role for Rab10 in Glut4 trafficking. Moreover, hyperinsulinemic-euglycemic clamp shows decreased whole-body glucose uptake as well as impaired suppression of hepatic glucose production in adipose Rab10 knockout mice. Thus, fully functional Glut4 vesicle trafficking in adipocytes is critical for maintaining insulin sensitivity. Comparative transcriptome analysis of perigonadal adipose tissue demonstrates significant transcriptional similarities between adipose Rab10 knockout mice and adipose Glut4 knockout mice, consistent with the notion that the phenotypic similarities between the two models are mediated by reduced insulin-stimulated glucose transport into adipocytes. Overall design: Transcriptome sequencing of perigonadal white adipose tissue
Publication Title
Disruption of Adipose Rab10-Dependent Insulin Signaling Causes Hepatic Insulin Resistance.
Sample Metadata Fields
No sample metadata fields
View Samples- Rattus norvegicus
- 8 Downloadable Samples
- Affymetrix Rat Gene 1.0 ST Array (ragene10st)
Description
In order to identify targets for HDAC4, NRVM were infected with adenoviral vectors encoding beta-Galactosidase or Flag- HDAC4, and incubated in serum free or 10% fetal calf serum containing growth medium for 48 hrs.
Publication Title
Modulation of chromatin position and gene expression by HDAC4 interaction with nucleoporins.
Sample Metadata Fields
Specimen part
View Samples- Mus musculus
- 18 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
Objective: Nonalcoholic fatty liver disease (NAFLD) is linked to obesity and diabetes, suggesting an important role of adipose tissue in the pathogenesis of NAFLD. Here we aim to investigate the interaction between adipose tissue and liver in NAFLD, and identify potential early plasma markers that predict NASH. Research Design and Methods: C57Bl/6 mice were chronically fed a high fat diet to induce NAFLD and compared with mice fed low fat diet. Extensive histological and phenotypical analyses coupled with a time-course study of plasma proteins using multiplex assay was performed. Results: Mice exhibited pronounced heterogeneity in liver histological scoring, leading to classification into 4 subgroups: LF-low (LFL) responders displaying normal liver morphology, LF-high (LFH) responders showing benign hepatic steatosis, HF-low (HFL) responders displaying pre-NASH with macrovesicular lipid droplets, and HF-high (HFH) responders exhibiting overt NASH characterized by ballooning of hepatocytes, presence of Mallory bodies, and activated inflammatory cells. Compared to HFL responders, HFH mice gained weight more rapidly and exhibited adipose tissue dysfunction characterized by decreased final fat mass, enhanced macrophage infiltration and inflammation, and adipose tissue remodelling. Plasma haptoglobin, IL-1, TIMP-1, adiponectin and leptin were significantly changed in HFH mice. Multivariate analysis indicated that in addition to leptin, plasma CRP, haptoglobin, eotaxin and MIP-1 early in the intervention were positively associated with liver triglycerides. Intermediate prognostic markers of liver triglycerides included IL-18, IL-1, MIP-1 and MIP-2, whereas insulin, TIMP-1, GCP-2 and MPO emerged as late markers. Conclusions: Our data support the existence of a tight relationship between adipose tissue dysfunction and NASH pathogenesis and point to several novel potential predictive biomarkers for NASH.
Publication Title
Adipose tissue dysfunction signals progression of hepatic steatosis towards nonalcoholic steatohepatitis in C57BL/6 mice.
Sample Metadata Fields
Specimen part
View Samples- Homo sapiens
- 9 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
We studied the KRAS and NRAS mutational status in pediatric MLL-AF4+ leukemia patients by means of ultra deep amplicon sequencing. The gene expression profiles of RAS wild type and RAS mutated patients were investigated by gene expression analysis. We showed that mutated patients were characterized by a RAS related expression signature.
Publication Title
Deciphering KRAS and NRAS mutated clone dynamics in MLL-AF4 paediatric leukaemia by ultra deep sequencing analysis.
Sample Metadata Fields
Specimen part, Disease, Disease stage, Subject
View Samples- Homo sapiens
- 8 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Glioblastoma (GBM) is the most devastating tumour of the brain, endowed with a fatal prognosis. Indeed, the complete eradication of cancer cell disseminated outside the GBM mass still remains a crucial issue. Given the reported strong association existing between Annexin 2A (ANXA2) expression and cell dissemination in many cancers, we evaluated the effects exerted by the modulation of ANXA2 levels in GBM cells and assessed its potential in predicting patient outcome. Here, we show that expression of ANXA2 positively correlates with metastatic gene signatures and demonstrates to be prognostic by itself. Indeed, we prove that ANXA2 is involved in cell migration, invasion, cytoskeletal remodeling and proliferation in GBM cells. Moreover, we were able to construct a gene signature representative of ANXA2 inhibition, which showed a significant prognostic potential in different GBM patient cohorts.
Publication Title
Annexin 2A sustains glioblastoma cell dissemination and proliferation.
Sample Metadata Fields
Specimen part
View Samples- Mus musculus
- 18 Downloadable Samples
- Affymetrix Mouse Gene 1.0 ST Array (mogene10st)
Description
Discrimination between self vs. non-self and adequate response to infection and tissue damage are fundamental functions of the immune system. The rapid and global spread of known and emerging viruses is a testament that the timely detection of viral pathogens that reproduce within host cells, presents a formidable challenge to the immune system. To gain access to a proper reproductive niche, many pathogens travel via the host vasculature and therefore become exposed to humoral factors of the innate immune system. Although a cascade of coagulation factors plays a fundamental role in host defense for living fossils such as horseshoe crabs (Xiphosurida spp), the role of the coagulation system in activation of innate responses to pathogens in higher organisms remains unclear. When human type C adenovirus (HAdv) enters the circulation, 240 copies of coagulation factor X (FX) bind to the virus particle with picomolar affinity. Here, using molecular dynamics flexible fitting (MDFF) and high resolution cryo-electron microscopy (cryo-EM), we defined the interface between the HAdv5 hexon protein and FX at pseudo-atomic level. Based on this structural data, we introduced a single amino acid substitution, T424A, in the hexon that completely abrogated FX interaction with the virus. In vivo genome-wide transcriptional profiling revealed that FX-binding-ablated virus failed to activate a distinct network of the early response genes, whose expression depends on transcription factor NFKB1. Deconvolution of the signaling network responsible for early gene activation showed that the FX-HAdv complex triggers MyD88/TRIF/TRAF6 signaling upon activation of toll-like receptor 4 (TLR4) that serves as a principal sensor of FX-virus complex in vivo. Our study implicates host factor decoration of the virus as a mechanism to trigger innate immune sensor that respond to a misplacement of coagulation FX from the blood into intracellular macrophage compartments upon virus entry into the cell. Our results further the mounting evidence of evolutionary conservation between the coagulation system and innate immunity.
Publication Title
Coagulation factor X activates innate immunity to human species C adenovirus.
Sample Metadata Fields
Specimen part, Treatment
View Samples