Polyinosinic:polycytidylic acid (poly I:C) is a synthetic analogue of double-stranded (ds)RNA, a molecular pattern associated with viral infections, that is used to exacerbate inflammation in lung injury models. Despite its frequent use, there are no detailed studies of the responses elicited by a single topical administration of poly I:C to the lungs of mice. Our data provides the first demonstration that the molecular responses in the airways induced by poly I:C correlate to those observed in the lungs of COPD patients. These expression data also revealed three distinct phases of response to poly I:C, consistent with the changing inflammatory cell infiltrate in the airways. Poly I:C induced increased numbers of neutrophils and NK cells in the airways, which were blocked by CXCR2 and CCR5 antagonists, respectively. Using gene set variation analysis on representative data sets, gene sets defined by poly I:C-induced DEGs were enriched in the molecular profiles of chronic obstructive pulmonary disease (COPD), but not idiopathic pulmonary fibrosis patients. Collectively, these data represent a new approach for validating the clinical relevance of preclinical animal models and demonstrate that a dual CXCR2/CCR5 antagonist may be an effective treatment for COPD patients.
Double-stranded RNA induces molecular and inflammatory signatures that are directly relevant to COPD.
Sex, Specimen part, Time
View SamplesGenomic profiling of bleomycin- and saline-treated mice across 7 timepoints (1, 2, 7, 14, 21, 28, 35 days post treatment) was carried out in C57BL6/J mice to determine the phases of response to bleomycin treatment which correspond to onset of active pulmonary fibrosis.
Bleomycin induces molecular changes directly relevant to idiopathic pulmonary fibrosis: a model for "active" disease.
Sex, Specimen part, Treatment, Time
View SamplesAnalysis of gene expression in lungs of C57BL/6J mice that develop chronic airway disease phenotypes after a single Sendai virus infection, compared with mice treated with UV-inactivated virus.
Persistent activation of an innate immune response translates respiratory viral infection into chronic lung disease.
Sex, Time
View SamplesAcetaminophen (APAP) is the most widely used analgesic in the United States. Its acute overdose causes liver damage by inducing localized centrilobular cell death. Because of widespread use, APAP toxicity has become the most frequent cause of acute liver failure. Many factors have been associated with the susceptibility of APAP-induced liver injuries, however, few of them have been confirmed and used in the clinical setting.
An integrative genomic analysis identifies Bhmt2 as a diet-dependent genetic factor protecting against acetaminophen-induced liver toxicity.
Specimen part, Time
View SamplesThe anti-diabetic drug and agonist of the peroxisome proliferator-activated receptor gamma (Pparg), rosiglitazone, was recently withdrawn in many countries because the drug use was associated with an increased risk of heart failure. To investigate underlying pathomechanisms, we chose 6-month-old apolipoprotein E (apoE)-deficient mice, which are prone to atherosclerosis and insulin resistance, and thereby mimic the risk profile of patients with cardiovascular disease. After 8 weeks of rosiglitazone treatment (30 mg/kg/day), echocardiography and histology analyses demonstrated that rosiglitazone had induced heart failure with cardiac dilation. Concomitantly, cardiac lipid overload and lipid-induced cardiomyocyte death developed. The microarray gene expression study of heart tissue from rosiglitazone-treated apoE-deficient mice relative to untreated apoE-deficient mice and non-transgenic B6 mice identified cardiac Pparg-dependent lipid metabolism genes in rosiglitazone-treated mice, which seem to trigger a major heart failure promoting pathway.
Inhibition of G-protein-coupled Receptor Kinase 2 Prevents the Dysfunctional Cardiac Substrate Metabolism in Fatty Acid Synthase Transgenic Mice.
Age, Specimen part, Treatment
View SamplesHypercholesterolemic APOE-deficient mice are a widely used experimental model of atherosclerosis and increased generation of reactive oxygen species (ROS) is a prominent feature of atherosclerosis development. To study the impact of ROS on atherogenesis, we treated APOE-deficient mice for 7 months with the antioxidant vitamin E (2000 IU/kg diet) and performed whole genome microarray gene expression profiling of aortic genes. Microarray gene expression profiling was performed of whole aortas isolated from vitamin E-treated APOE-deficient relative to untreated APOE-deficient mice with overt atherosclerosis, and nontransgenic B6 control mice. Microarray gene expression profiling revealed that vitamin E treatment prevented atherosclerosis-related gene expression changes of the aortic intima and media.
Microarray gene expression profiling reveals antioxidant-like effects of angiotensin II inhibition in atherosclerosis.
Specimen part, Disease, Treatment
View SamplesThe Raf kinase inhibitor protein (RKIP) is a dual inhibitor of the Raf kinase and the G-protein-coupled receptor kinase 2 (GRK2). GRK2 is an indispensable kinase, which exerts a major role in the pathogenesis of heart failure, and inhibition of GRK2 is cardioprotective in experimental models of heart failure. To investigate the cardiac function of RKIP as GRK2 inhibitor, we generated transgenic mice with myocardium-specific expression of RKIP under control of the alpha-MHC promoter. For comparison, mice with myocardium-specific expression of a GRK-specific peptide inhibitor (GRK-Inh) were also generated. Two different transgenic mouse models were established. Transgenic RKIP mice and transgenic GRK-Inh mice were born at Mendelian frequencey and grew to adulthood normally.
Inhibition of G-protein-coupled receptor kinase 2 (GRK2) triggers the growth-promoting mitogen-activated protein kinase (MAPK) pathway.
Sex, Age, Specimen part
View SamplesSphingosine 1-phosphate (S1P) is a bioactive lipid whose levels are tightly regulated by its synthesis and degradation. Intracellularly, S1P is dephosphoryled by the actions of two S1P-specific phosphatases, sphingosine 1-phosphate phosphatase 1 and 2. To identify the physiologic functions of S1P phosphatase 1, we have studied mice with its gene, Sgpp1, deleted. Sgpp1-/- mice appeared normal at birth but during the first week of life, they exhibited stunted growth, suffered desquamation, and most died before weaning. Interestingly, the epidermal permeability barrier developed normally during embryogenesis. Sgpp1 -/- pups and surviving adults exhibited epidermal hyperplasia and abnormal expression of keratinocyte differentiation markers. Keratinocytes isolated from Sgpp1 -/- skin had increased intracellular S1P levels, and expressed a gene expression profile that indicated enhanced differentiation. The results reveal S1P metabolism as a regulator of keratinocyte differentiation and epidermal homeostasis.
Sphingosine-1-phosphate phosphatase 1 regulates keratinocyte differentiation and epidermal homeostasis.
Specimen part
View SamplesWe used a novel probe-level microarray analysis, revealing connections between mRNA processing and lymphoid neoplasia, in a mouse leukemia model. Characteristic differences in mRNA processing, primarily in the 3-untranslated region, distinguished histologically similar tumor subtypes with different survival characteristics. Gene sets with specific processing in each tumor subtype defined signatures useful for tumor subclassification, as demonstrated by internal cross-validation with up to 80% discrimination accuracy. A combination of mRNA expression and sequence analysis suggested that differences in isoform abundance likely arose from both alternative polyadenylation and differential degradation.
Global changes in processing of mRNA 3' untranslated regions characterize clinically distinct cancer subtypes.
Specimen part
View SamplesThe goal was to determine how IL-12 affects gene expression by murine CTL.
IL-12 enhances CTL synapse formation and induces self-reactivity.
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