Autism Spectrum Disorder (ASD) is a common pediatric cognitive disorder with high heritability. Yet no single genetic variant has accounted for more than a small fraction of cases. We sought to determine whether we could classify patients as having ASD vs. controls solely based on a multi-gene expression profiling of their peripheral blood cells.
Characteristics and predictive value of blood transcriptome signature in males with autism spectrum disorders.
Sex, Disease, Race
View SamplesThe purpose of the experiment was to generate a time course of gene expression following irradiation. The goal was then to model this data to extract hidden variables - chiefly, the activity profiles of the p53 transcription factor. Using this information the aim was to predict which transcripts changed by IR were targets of p53. Cells in log phase (1 x 106 ml-1) were ?-irradiated with 5 Gy at room temperature (RT) at a dose rate of 2.45 Gy per minute with a 137Cs ?-irradiator. Cells were harvested at 0, 2, 4, 6, 8, 10 and 12 hours, and RNA and protein were extracted (Trizol, Invitrogen). Affymetrix U133A arrays were hybridized as standard (www.affymetrix.co.uk). Array quality was determined using R and GCOS .rpt file values. The time course was replicated three times from independent cell preparations.
Ranked prediction of p53 targets using hidden variable dynamic modeling.
Specimen part, Disease, Cell line, Time
View SamplesWe performed gene expression profiling of oligooxopiperazines (OPs) targeting the hypoxia-inducible transcription factor complex. Treatment of cells with OPs inhibited hypoxia-inducible gene expression in A549 cells.
In vivo modulation of hypoxia-inducible signaling by topographical helix mimetics.
Cell line
View Sampleseffect of overexpression of GATA-6 in P19 CL6 induced cells
Wnt2 is a direct downstream target of GATA6 during early cardiogenesis.
Cell line
View SamplesChronic alcohol ingestion changes the alveolar landscape. We used microarrays to characterize the change in mRNA expression following chronic alcohol ingestion in male Sprague Dawley rates (EtOH 36% of calories)
Chronic ethanol exposure alters the lung proteome and leads to mitochondrial dysfunction in alveolar type 2 cells.
Sex, Specimen part
View SamplesAlthough glucocorticoids (GCs) are known to exert numerous effects in the hippocampus, their chronic regulatory functions remain poorly understood. Moreover, evidence is inconsistent regarding the longstanding hypothesis that chronic GC exposure promotes brain aging/Alzheimer's disease. Here, we adrenalectomized male F344 rats at 15-months-of-age, maintained them for 3 months with implanted corticosterone (CORT) pellets producing low or intermediate (glucocorticoid-receptor (GR)-activating) blood levels of CORT, and performed microarray/pathway analyses in hippocampal CA1. We defined the chronic GC-dependent transcriptome as 393 genes that exhibited differential expression between Intermediate- and Low-CORT groups. Short-term CORT (4 days) did not recapitulate this transcriptome. Functional processes/pathways overrepresented by chronic CORT-upregulated genes included learning/plasticity, differentiation, glucose metabolism and cholesterol biosynthesis, whereas processes overrepresented by CORT-downregulated genes included inflammatory/immune/glial responses and extracellular structure. These profiles indicate that GCs chronically activate neuronal/metabolic processes while coordinately repressing a glial axis of reactivity/inflammation. We then compared the GC-transcriptome with a previously-defined hippocampal aging transcriptome, revealing a high proportion of common genes. Although CORT and aging moved expression of some common genes in the same-direction, the majority were shifted in opposite directions by CORT and aging (e.g., glial inflammatory genes downregulated by CORT are upregulated with aging). These results contradict the hypothesis that GCs simply promote brain aging, and also suggest that the opposite-direction shifts during aging reflect resistance to CORT regulation. Therefore, we propose a new model in which aging-related GC resistance develops in some target pathways while GC overstimulation develops in others, together generating much of the brain aging phenotype.
Glucocorticoid-dependent hippocampal transcriptome in male rats: pathway-specific alterations with aging.
Sex, Age, Specimen part
View SamplesVitamin 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.
Vitamin D prevents cognitive decline and enhances hippocampal synaptic function in aging rats.
Sex, Specimen part
View SamplesSleep deprivation (SD) in young adults is associated with metabolic, stress and cognitive responses that are also characteristic of brain aging. Given that sleep architecture changes with age, including increased fragmentation and decreased slow wave activity, it seems reasonable to investigate potential molecular relationships between SD and aging in brain tissue. Here, we tested the hypothesis that young rats exposed to 24 or 72 hour SD would respond with stress and aging-like shifts in brain hippocampal CA1 gene expression. SD animals showed blood corticosterone and weight changes consistent with a stress response. Microarray results, validated by Western blot and comparison to prior SD studies, pointed to disruptions in neurotransmission, sleep pressure signaling, and macromolecular synthesis. In a separate experiment, animals exposed to 24 or 72 hour novel environment stress recapitulated nearly one third of the SD transcriptional profile, particularly upregulated apoptotic and immune signaling pathways. Compared to aging (based on three previously published independent hippocampal aging studies), SD transcriptional profiles agreed for neurogenesis and energy pathways. However, immune signaling, glial activity, macromolecular synthesis and neuronal function all showed an SD profile that was, at least in part, opposed by aging. We conclude that while stress and SD have discrete molecular signatures, they do show a subset of highly similar changes. However, the same could not be said of aging and SD, where a similar subset of genes is changed, but in partially divergent directions. Finally, this work identifies presynaptic vesicular release and intercellular adhesion molecular signatures as novel targets for future SD-countering therapeutics.
Hippocampal CA1 transcriptional profile of sleep deprivation: relation to aging and stress.
Sex, Treatment
View SamplesChanges in the transcript profile due to ABCA1 expression in murine liver samples was evaluated in LDL receptor -/- genetic backgrounds.
ABCA1 overexpression in the liver of LDLr-KO mice leads to accumulation of pro-atherogenic lipoproteins and enhanced atherosclerosis.
Sex, Specimen part
View SamplesMaternal Blood histamine levels are tightly controlled in normal pregnancy. However, in specific complications of human pregnancy such as pre-eclampsia the levels of both placental and maternal blood histamine increase. Increasing blood histamine levels nonetheless, have been associated with oxidative stress, endothelial dysfunction, abnormal tissue growth, and Th1/TH2 imbalance, which are also linked to pre-eclampsia. Little is known of the molecular responses in the placenta to the prolonged exposure to increasing histamine levels in the presence of changing oxygen concentrations.
Oxygen and tissue culture affect placental gene expression.
Specimen part, Treatment
View Samples