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GSE18920
Homo sapiens
43 Downloadable Samples
Affymetrix Human Exon 1.0 ST Array [probe set (exon) version (huex10st)
Description
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive weakness from loss of motor neurons. The fundamental pathogenic mechanisms are unknown and recent evidence is implicating a significant role for abnormal exon splicing and RNA processing. Using new comprehensive genomic technologies, we studied exon splicing directly in 12 sporadic ALS and 10 control lumbar spinal cords acquired by a rapid autopsy system that processed nervous systems specifically for genomic studies. ALS patients had rostral onset and caudally advancing disease and abundant residual motor neurons in this region. We created two RNA pools, one from motor neurons collected by laser capture microdissection and one from the surrounding anterior horns. From each, we isolated RNA, amplified mRNA, profiled whole-genome exon splicing, and applied advanced bioinformatics. We employed rigorous quality control measures at all steps and validated findings by qPCR. In the motor neuron enriched mRNA pool, we found two distinct cohorts of mRNA signals, most of which were up-regulated: 148 differentially expressed genes (p103) and 411 aberrantly spliced genes (p105). The aberrantly spliced genes were highly enriched in cell adhesion (p1057), especially cell-matrix as opposed to cell-cell adhesion. Most of the enriching genes encode transmembrane or secreted as opposed to nuclear or cytoplasmic proteins. The differentially expressed genes were not biologically enriched. In the anterior horn enriched mRNA pool, we could not clearly identify mRNA signals or biological enrichment. These findings, perturbed and up-regulated cell-matrix adhesion, suggest possible mechanisms for the contiguously progressive nature of motor neuron degeneration.
Publication Title
Sporadic ALS has compartment-specific aberrant exon splicing and altered cell-matrix adhesion biology.
Sample Metadata Fields
Sex, Age, Specimen part
View Samples- Mus musculus
- 108 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
In this study that was specifically designed to identify early stages of glaucoma in DBA/2J mice, we used genome-wide expression profiling and a series of computational methods. Our methods successfully subdivided eyes with no detectable glaucoma by conventional assays into molecularly defined stages of disease. These stages represent a temporally ordered sequence of glaucoma states. Using an array of tools, we then determined networks and biological processes that are altered at these early stages. Our strategy proved very sensitive, suggesting that similar approaches will be valuable for uncovering early processes in other complex, later-onset diseases. Early changes included upregulation of both the complement cascade and endothelin system, and so we tested the therapeutic value of separately inhibiting them. Mice with a mutation in the complement component 1a gene (C1qa) were robustly protected from glaucoma with the protection being among the greatest reported. Similarly, inhibition of the endothelin system was strongly protective. Since EDN2 is potently vasoconstrictive and was produced by microglial/macrophages, our data provide a novel link between these cell types and vascular dysfunction in glaucoma. Targeting early events such as the upregulation of the complement and endothelin pathways may provide effective new treatments for human glaucoma.
Publication Title
Molecular clustering identifies complement and endothelin induction as early events in a mouse model of glaucoma.
Sample Metadata Fields
Sex, Age, Specimen part
View Samples- Mus musculus
- 49 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
Glaucoma is a common ocular disorder that is a leading cause of blindness worldwide. It is characterized by the dysfunction and loss of retinal ganglion cells (RGCs). Although many studies have implicated various molecules in glaucoma, no mechanism has been shown to be responsible for the earliest detectable damage to RGCs and their axons in the optic nerve. Here, we show that the leukocyte transendothelial migration pathway is activated in the optic nerve head at the earliest stages of disease in an inherited mouse model of glaucoma. This resulted in proinflammatory monocytes entering the optic nerve prior to detectable neuronal damage. A 1-time x-ray treatment prevented monocyte entry and subsequent glaucomatous damage. A single x-ray treatment of an individual eye in young mice provided that eye with long-term protection from glaucoma but had no effect on the contralateral eye. Localized radiation treatment prevented detectable neuronal damage and dysfunction in treated eyes, despite the continued presence of other glaucomatous stresses and signaling pathways. Injection of endothelin-2, a damaging mediator produced by the monocytes, into irradiated eyes, combined with the other glaucomatous stresses, restored neural damage with a topography characteristic of glaucoma. Together, these data support a model of glaucomatous damage involving monocyte entry into the optic nerve. Genome-wide assessment of gene expression changes was performed in DBA/2J-Gpnmb+, DBA/2J mice and irradiated DBA/2J mice at 8.5 and 10.5 months of age.
Publication Title
Radiation treatment inhibits monocyte entry into the optic nerve head and prevents neuronal damage in a mouse model of glaucoma.
Sample Metadata Fields
Sex
View Samples- Homo sapiens
- 8 Downloadable Samples
- Affymetrix Human Genome U133A Array (hgu133a)
Description
Focal nodular hyperplasias (FNHs) are benign liver lesions considered to be a hyperplastic response to increased blood flow in otherwise normal liver. In contrast, FNH-like nodules occur in cirrhotic liver but share similar histopathological features. To better understand the pathophysiology of FNH, we performed a transcriptomic analysis. Methods: Affymetrix and cDNA microarrays were used to compare gene expression in eight FNHs with that in tissue from six normal livers. Selected genes were validated with quantitative RT-PCR in 70 benign liver tumors including adenomas and cirrhotic and FNH-like lesions. Results: Among the deregulated genes in FNHs, 19 were physiologically zonated in the normal liver lobule. All six periveinous genes were up-regulated in FNH, whereas 13 genes normally expressed in the periportal area were down-regulated. Immunohistochemistry revealed that glutamine synthetase was markedly overexpressed, forming anastomosed areas usually centered on visible veins. -catenin mRNA was slightly but significantly overexpressed, as were several known -catenin target genes. Moreover, activated hypophosphorylated -catenin protein accumulated in FNH in the absence of activating mutations. These results suggest zonated activation of the -catenin pathway specifically in FNH, whereas the other benign hepatocellular tumors, including FNH-like lesions, demonstrated an entirely different pattern of -catenin expression. Conclusions: In FNH, increased expression of the -catenin pathway was restricted to enlarged periveinous areas, which may explain the slight polyclonal over-proliferation of hepatocytes at the origin of the lesion. FNH-like nodules may have a different pathogenetic origin.
Publication Title
The beta-catenin pathway is activated in focal nodular hyperplasia but not in cirrhotic FNH-like nodules.
Sample Metadata Fields
Sex, Specimen part, Disease
View Samples- Mus musculus
- 6 Downloadable Samples
- Affymetrix Mouse Gene 2.0 ST Array (mogene20st)
Description
Comparative analysis of FACS-sorted CCR2- and CCR2+ HSC in the steady state. CCR2+ HSC have fourfold higher proliferative rates than CCR2- HSC, are are biased towards the myeloid lineage and dominate the migratory HSC population.
Publication Title
Myocardial Infarction Activates CCR2(+) Hematopoietic Stem and Progenitor Cells.
Sample Metadata Fields
Specimen part
View Samples- Mus musculus
- 6 Downloadable Samples
- Affymetrix Mouse Gene 1.0 ST Array (mogene10st)
Description
Normal arteries contain a large population of tissue resident macrophages (M). Their origins, as well as the mechanisms that sustain them during homeostasis and disease, however, are poorly understood. Gene expression profiling, we show, identifies arterial M as a distinct population among tissue M. Ontologically, arterial M arise before birth, though CX3CR1-, Csf1r-, and Flt3-driven fate mapping approaches demonstrate M colonization occurs through successive contributions of yolk sac (YS) and conventional hematopoiesis. In adulthood, arterial M renewal is driven by local proliferation rather than monocyte recruitment from the blood. Proliferation sustains M not only during steady state conditions, but mediates their rebound after severe depletion following sepsis. Importantly, the return of arterial M to functional homeostasis after infection is rapid; repopulated M exhibit a transcriptional program similar to resting M and efficiently phagocytose bacteria. Collectively, our data provide a detailed framework for future studies of arterial M function in health and disease.
Publication Title
Self-renewing resident arterial macrophages arise from embryonic CX3CR1(+) precursors and circulating monocytes immediately after birth.
Sample Metadata Fields
Sex, Specimen part
View Samples- Mus musculus
- 226 Downloadable Samples
NextSeq 500
Description
Molecular heterogeneity among spiral ganglion neurons (SGNs) in the mouse cochlea was investigated in two genetic backgrounds: 1) wildtype, 2) Vglut3-/-, which lack inner hair cell-driven glutamatergic activation of SGNs. Overall design: Individual spiral-ganglion neurons expressing the fluorescent reporter tdTomato were dissociated and manually placed into PCR tubes; single-cell libraries were made by the Smart-seq2 approach; sequencing was done using the NextSeq platform (Illumina) at an average read depth of 4.5 million; bioinformatic analysis was conducted in R. Genotypes: bhlhb5::cre/+; Ai14/+ (wildtype) and bhlhb5::cre/+;Ai14/+; Vglut3-/- (Vglut3-/-). Age: P25-P27
Publication Title
Sensory Neuron Diversity in the Inner Ear Is Shaped by Activity.
Sample Metadata Fields
Subject
View Samples- Mus musculus
- 32 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
Normal adult liver is uniquely capable of renewal
Publication Title
Restoration of liver mass after injury requires proliferative and not embryonic transcriptional patterns.
Sample Metadata Fields
Age
View Samples- Mus musculus
- 12 Downloadable Samples
- Illumina MouseWG-6 v2.0 expression beadchip
Description
Nrf2 is an important therapeutic target as activation of this pathway detoxifies harmful insults and reduces oxidative stress. However, the role of Nrf2 in cancer biology is controversial. Protection against oxidative stress and inflammation can confer a survival advantage to tumor cells, leading to a poor prognosis, and constitutive activation of Nrf2 has been detected in numerous tumors. In our study, we examined the role of two clinically relevant classes of Nrf2 activators, the synthetic triterpenoids (CDDO-Im and CDDO-Me) and dimethyl fumarate (DMF) in lung cancer.
Publication Title
Dimethyl fumarate and the oleanane triterpenoids, CDDO-imidazolide and CDDO-methyl ester, both activate the Nrf2 pathway but have opposite effects in the A/J model of lung carcinogenesis.
Sample Metadata Fields
Sex, Specimen part
View Samples- Homo sapiens
- 4 Downloadable Samples
- Affymetrix HT Human Genome U133A Array (hthgu133a)
Description
While early stages of clear cell renal cell carcinoma (ccRCC) are curable, survival outcome for metastatic ccRCC remains poor. The purpose of the current study was to apply a new individualized bioinformatics analysis (IBA) strategy to these transcriptome data in conjunction with Gene Set Enrichment Analysis of the Connectivity Map (C-MAP) database to identify and reposition FDA-approved drugs for anti-cancer therapy. We demonstrated that one of the drugs predicted to revert the RCC gene signature towards normal kidney, pentamidine, is effective against RCC cells in culture and in a RCC xenograft model. Most importantly, pentamidine slows tumor growth in the 786-O human ccRCC xenograft mouse model. To determine which genes are regulated by pentamidine in a human RCC cell line, 786-O, we treated these cells with pentamidine and performed transcriptional profiling analysis.
Publication Title
Computational repositioning and preclinical validation of pentamidine for renal cell cancer.
Sample Metadata Fields
Cell line, Treatment
View Samples