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GSE24515
Rattus norvegicus
12 Downloadable Samples
Affymetrix Rat Genome 230 2.0 Array (rat2302)
Description
Background: Age-related cognitive deficits negatively affect quality of life and can presage serious neurodegenerative disorders. Despite sleep disruptions well-recognized negative influence on cognition, and its prevalence with age, surprisingly few studies have tested sleeps relationship to cognitive aging.
Publication Title
Deep sleep and parietal cortex gene expression changes are related to cognitive deficits with age.
Sample Metadata Fields
Sex, Age, Specimen part, Subject
View Samples- Rattus norvegicus
- 26 Downloadable Samples
- Affymetrix Rat Gene 1.0 ST Array (ragene10st)
Description
Vitamin D is an important calcium-regulating hormone with diverse functions in numerous tissues including the brain. Increasing evidence suggests that vitamin D may play a role in maintaining cognitive function and that vitamin D deficiency may accelerate age-related cognitive decline. Using aging rodents, we attempted to model the range of human serum vitamin D levels, from deficient to sufficient, to test whether vitamin D could preserve or improve cognitive function with aging. For 5-6 months, middle-aged F344 rats were fed diets containing low, medium (typical amount) or high vitamin D3 (100, 1000 or 10,000 IU/kg diet, respectively) and then hippocampal-dependent learning and memory were tested in the Morris water maze. Rats on high vitamin D achieved the highest blood levels (in the sufficient range) and significantly outperformed low and medium groups on maze reversal, a particularly challenging task that detects more subtle changes in memory. In addition to calcium-related processes, hippocampal gene expression microarrays identified pathways pertaining to synaptic transmission, cell communication and G-protein function as being up-regulated with high vitamin D. Basal synaptic transmission also was enhanced corroborating observed effects on gene expression and learning and memory. Our studies demonstrate a causal relationship between vitamin D status and cognitive function and suggest that vitamin D-mediated changes in hippocampal gene expression may improve the likelihood of successful brain aging.
Publication Title
Vitamin D prevents cognitive decline and enhances hippocampal synaptic function in aging rats.
Sample Metadata Fields
Sex, Specimen part
View Samples- Rattus norvegicus
- 29 Downloadable Samples
- Affymetrix Rat Genome 230 2.0 Array (rat2302)
Description
Background: Thiazolidinediones (TZDs) activate peroxisome proliferator-activated receptor gamma (PPARgamma) and are used clinically to help restore peripheral insulin sensitivity in Type 2 diabetes (T2DM). Interestingly, long-term treatment of mouse models of Alzheimers disease (AD) with TZDs also has been shown to reduce several well-established brain biomarkers of AD including inflammation, oxidative stress and Abeta accumulation. While some of the TZD actions are becoming clear in AD models and may mediate their reported beneficial impact in AD patients, little is known about the functional consequences of TZDs in animal models of normal aging. Because aging is a common risk factor for both AD and T2DM, we investigated whether the TZD, pioglitazone could alter brain aging under non-pathological conditions. Findings: The TZD pioglitazone (PIO) was incorporated into the diet to yield a final dose of approximately 2.3 mg/kg body weight/day. PIO reduced insulin levels irrespective of age. Interestingly, a significant reduction in the Ca2+-dependent afterhyperpolarization was seen in the aged animals with no significant change in LTP maintenance or learning and memory performance. Finally, a combination of microarray analyses on hippocampal tissue and serum-based multiplex cytokine assays revealed that age-dependent inflammatory changes in brain and periphery were not reversed by PIO.
Publication Title
Effects of long-term pioglitazone treatment on peripheral and central markers of aging.
Sample Metadata Fields
Sex, Age
View Samples- Mus musculus
- 16 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
Thiazolidinediones (TZDs) are agonists at peroxisome proliferator-activated gamma-type (PPAR-y) receptors and are used clinically for the treatment of type 2 diabetes where they have been shown to reestablish insulin sensitivity, improve lipids profile, and reduce inflammation. Recent work also suggests that TZDs may be beneficial in Alzheimer's disease (AD), ameliorating cognitive decline early in the disease process. However, there have been only a few studies identifying mechanisms through which cognitive benefits may be exerted. Starting at 10 months of age, the triple transgenic mouse model of AD (3xTg-AD) with accelerated amyloid-B (AB) deposition and tau pathology was treated with the TZD pioglitazone (PIO- Actos) at 18 mg/Kg body weight/day. After four months, PIO-treated animals showed multiple beneficial effects, including improved learning on the active avoidance task, reduced serum cholesterol, decreased hippocampal AB deposits, and enhanced short- and long-term plasticity. Baseline electrophysiological membrane properties and blood glucose levels were unchanged by PIO treatment. Gene microarray analyses of hippocampal tissue identified predicted transcriptional responses following TZD treatment as well as potentially novel targets of TZDs, including facilitation of estrogenic processes, and decreases in glutamatergic and ketone metabolic/ cholesterol dependent processes. Taken together, these results confirm prior animal studies showing that TZDs can ameliorate cognitive deficits associated with AD-related pathology, but also extend these findings by pointing to novel molecular targets in the brain.
Publication Title
Long-term pioglitazone treatment improves learning and attenuates pathological markers in a mouse model of Alzheimer's disease.
Sample Metadata Fields
Sex, Age
View Samples- Homo sapiens
- 364 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Cellular and tissue defects associated with insulin resistance are coincident with transcriptional abnormalities and are improved after insulin sensitization with thiazolidinedione (TZD) PPAR ligands.
Publication Title
Mechanisms of human insulin resistance and thiazolidinedione-mediated insulin sensitization.
Sample Metadata Fields
Specimen part, Subject
View Samples- Rattus norvegicus
- 53 Downloadable Samples
- Affymetrix Rat Expression 230A Array (rae230a)
Description
We characterized the insulin sensitivity and multi-tissue gene expression profiles of lean and insulin resistant, obese Zucker rats untreated or treated with one of four PPAR ligands (pioglitazone, rosiglitazone, troglitazone, and AG035029). We analyzed the transcriptional profiles of adipose tissue, skeletal muscle, and liver from the rats and determined whether ligand insulin-sensitizing potency was related to ligand-induced alteration of functional pathways. Ligand treatments improved insulin sensitivity in obese rats, albeit to varying degrees.
Publication Title
Multi-tissue, selective PPARγ modulation of insulin sensitivity and metabolic pathways in obese rats.
Sample Metadata Fields
Sex, Specimen part
View Samples- Homo sapiens
- 4 Downloadable Samples
IlluminaHiSeq2000
Description
The goal of this study was to determine the transcriptional changes associated with breast cancer cells undergoing vascular mimicry in a 3D assay. Two breast cancer cell lines were plated on matrigel in the presence or absence of serum. MDA-MB-231 cells undergo vascular mimicry on matrigel in the absence of serum, MDA-MB-453 cells do not. Overall design: Four samples were analyzed. MDA-MB-231 and MDA-MB-453 cells were plated for 24 hours on matrigel in the presence or absence of serum. MDA-MB-231 cells undergo vascular mimicry when plated on matrigel in the absence of serum, while MDA-MB-453 cells do not.
Publication Title
ZEB1-repressed microRNAs inhibit autocrine signaling that promotes vascular mimicry of breast cancer cells.
Sample Metadata Fields
No sample metadata fields
View Samples- Homo sapiens
- 5 Downloadable Samples
- IlluminaHiSeq2000
Description
Inhibition of SET by siRNA or SET antagonist and CIP2A by siRNA can downregulate c-MYC and c-MYC target genes. Overall design: Cells were treated with a SET antagonist (1µMOP449) for 12 hours, or siRNA for 48 hours.
Publication Title
Targeting c-MYC by antagonizing PP2A inhibitors in breast cancer.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 35 Downloadable Samples
- Illumina HiSeq 2500
Description
Retinopathy of prematurity (ROP) is the most common cause of childhood blindness worldwide and is caused by oxygen therapy necessary to prevent mortality after premature birth. We have previously demonstrated the efficacy of systemic hypoxia inducible factor (HIF) stabilization through HIF prolyl hydroxylase inhibition (HIF PHi) in protecting retinal vasculature from oxygen toxicity in a mouse model of ROP or oxygen induced retinopathy (OIR). We definitively demonstrated that hepatic HIF-1 can be activated to confer this protection using systemic dimethyloxalylglycine (DMOG) to prevent HIF-1a degradation. In this study we compare Roxadustat, a small molecule stabilizer of HIF-1 currently in phase 3 clinical trials for increasing erythropoiesis in adult patients with chronic kidney disease, to DMOG. We demonstrate that Roxadustat induces vascular protection during hyperoxia to induce the coordinated sequential growth of retinal vasculature with a 3-fold reduction in oxygen induced capillary loss (p-=0.001). In order to define the molecular mechanism of protection, we further compared the transcriptome of both liver and retina after systemic treatment with Roxadustat or DMOG. Similar gene expression profiles were identified in liver but very different effects on transcription were found in retinal tissues because Roxadustat, in contrast to DMOG, directly targets retina, confirmed by western blot and by rescue of the hepatic HIF-1 KO, two criteria that DMOG treatment is unable to fulfill. Systems pharmacologic analysis demonstrates that Roxadustat induces typical HIF regulated genes critical to aerobic glycolysis in liver and retinal tissues whereas DMOG, acting through either secreted hepatokines or by influence of systemic DMOG, downregulates cell adhesion/extracellular matrix interaction pathways while increasing expression of histone cluster genes. Stratification of liver transcriptomes to secreted gene products again shows close consensus of hepatic genes induced by both small molecules, and includes upregulation of a plethora of angiogenic proteins such as plasminogen activator inhibitor (PAI-1), erythropoietin (EPO), and orosomucosoid 2 (ORM2). Secondary validation of these transcripts by serum ELISA confirms secretion of EPO and PAI-1 into blood from liver. These findings definitively demonstrate that HIF stabilization can prevent OIR by two pathways: direct retinal HIF stabilization and induction of aerobic glycolysis or indirect, hepatic HIF-1 stabilization and increased serum angiokines. Systems pharmacology analysis therefore explains why intermittent, low dosage of small molecule HIF stabilizers creates a profound protective phenotype, because both pathways can take advantage of cytoprotection induced by the liver and by retina synergistically. These data provide a rationale for considering low dose, intermittent systemic administration of Roxadustat, currently in phase 3 trials in adults with chronic kidney disease, to eradicate ROP in children. Overall design: RNA-Seq of mice treated with PBS (control), DMOG, or Roxadustat from liver or retina.
Publication Title
Comparative systems pharmacology of HIF stabilization in the prevention of retinopathy of prematurity.
Sample Metadata Fields
Specimen part, Cell line, Treatment, Subject
View Samples- Homo sapiens
- 20 Downloadable Samples
- Affymetrix Human Exon 1.0 ST Array [transcript (gene) version (huex10st)
Description
Cigarette smoking is the leading cause of emphysema in the United States. Alveolar macrophages play a critical role in the inflammation-mediated remodeling of the lung parenchyma in emphysema. However, the exact gene pathways and the role of DNA methylation in moderating this pathological transformation are not known. In order to more exactly understand this process, we compared genome-wide expression and methylation signatures of alveolar macrophages isolated from heavy smokers with those isolated from non-smoking controls. We found enrichment of differential methylation in genes from immune system and inflammatory pathways as determined by standard pathway analysis. Consistent with recent findings, significant methylation changes were particularly enriched in the areas flanking CpG islands (CpG shores). Analysis of matching gene expression data demonstrated a parallel enrichment for changes in immune system and inflammatory pathways. We conclude that alveolar macrophages from the lungs of smokers demonstrate coordinated changes in DNA methylation and gene expression that link to inflammation pathways. We suggest that further studies of DNA methylation in immune and inflammation-related gene expression are needed to understand the pathogenesis of emphysema and other smoking-related diseases.
Publication Title
Coordinated DNA methylation and gene expression changes in smoker alveolar macrophages: specific effects on VEGF receptor 1 expression.
Sample Metadata Fields
Specimen part, Disease
View Samples