Background
Expression quantitative trait loci mapping identifies new genetic models of glutathione S-transferase variation.
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View SamplesBoth the mechanism of action and the factors determining the behavioral response to antidepressants are unknown. It has been shown that antidepressant treatment promotes the proliferation and survival of hippocampal neurons via enhanced serotonergic signaling, but it is still unclear whether hippocampal neurogenesis is responsible for the behavioral response to antidepressants. Furthermore, a large subpopulation of patients fails to respond to antidepressant treatment due to presumed underlying genetic factors. In the present study, we have used the phenotypic and genotypic variability of inbred mouse strains to show that there is a genetic component to both the behavioral and neurogenic effects of chronic fluoxetine treatment, and that this antidepressant induces an increase in hippocampal cell proliferation only in the strains that also show a positive behavioral response to treatment. The behavioral and neurogenic responses are associated with an upregulation of genes known to promote neuronal proliferation and survival. These results suggest that inherent genetic predisposition to increased serotonin-induced neurogenesis is a determinant of antidepressant efficacy.
Genetic regulation of behavioral and neuronal responses to fluoxetine.
Sex, Treatment
View SamplesIn addition to their stem/progenitor properties, mesenchymal stem cells (MSCs) also exhibit various effector functions potent effector (angiogenic, anti-inflammatory, immune-modulatory) functions that are largely paracrine in nature. It is widely believed that effector functions underlie most of the therapeutic potential of MSCs and are independent of their stem/progenitor properties. Here we demonstrate that stem/progenitor and effector functions are coordinately regulated at the cellular level by the transcription factor Twist1 and specified within populations according to a hierarchical model. We further show that manipulation of Twist1 levels by genetic approaches or by exposure to widely used culture supplements including fibroblast growth factor 2 (Ffg2) and interferon gamma (IFN-gamma) alters MSC efficacy in cell-based and in vivo assays in a predictable manner. Thus, by mechanistically linking stem/progenitor and effector functions our studies provide a unifying framework in the form of an MSC hierarchy that models the functional complexity of populations. Using this framework, we developed a Clinical Indications Prediction (CLIP) scale that predicts how donor-to-donor heterogeneity and culture conditions impact the therapeutic efficacy of MSC populations for different disease indications.
No associated publication
Specimen part
View SamplesMicroRNAs (miRNAs) regulate many basic aspects of cell biology including neuronal plasticity, but little is known of their roles in drug addiction. Extended access to cocaine can trigger the emergence of compulsive drug-seeking behaviors, but molecular mechanisms regulating this process remain unclear. Here we report that microRNA-212 (miR-212) is upregulated in the dorsal striatum of rats with extended access to cocaine. Striatal overexpression of miR-212 decreases, whereas its inhibition increases cocaine intake in rats with extended but not restricted drug access, suggesting that miR-212 serves as a protective factor against the development of compulsive drug seeking. The transcription factor CREB (cAMP response element-binding protein) is considered a core regulator of cocaine reward. We show that miR-212 controls responsiveness to cocaine by dramatically amplifying striatal CREB signaling. This action occurs through miR-212-enhanced Raf-1 activity, resulting in adenylyl cyclase sensitization and increased expression of the essential CREB co-activator TORC (Transducer of Regulated CREB; also known as CRTC). Our findings suggest that striatal miR-212 signaling plays a key role in vulnerability to addiction, and that noncoding RNAs such as the miRNAs may serve as novel targets for the development of anti-addiction therapeutics.
Striatal microRNA controls cocaine intake through CREB signalling.
Sex, Specimen part, Cell line
View SamplesAging is associated with a decline in hippocampal mediated learning and memory, a process wich can be ameliorated by dietary (caloric) restriction. We used Affymetrix gene expression analysis to monitor changes in three regions of the hippocampus (CA1, CA3, DG) of middle aged (18 months) and old (28 month) rats that were exposed to dietary restriction. Old rats were determined to be good performers (GP) or poor performers (PP) in behavioral tests to assess thier hippocampal function.
Gene expression in the hippocampus: regionally specific effects of aging and caloric restriction.
Age, Specimen part
View SamplesThis SuperSeries is composed of the SubSeries listed below.
No associated publication
Age, Specimen part
View SamplesExtreme hypobaria is a novel abiotic stress that is outside the evolutionary experience of terrestrial plants. In natural environments, the practical limit of atmospheric pressure experienced by higher plants is about 50 kPa or ~.5 atmospheres; a limit that is primarily imposed by the combined stresses inherent to high altitude conditions of terrestrial mountains. However, in highly controlled chambers and within extra-terrestrial greenhouses the atmospheric pressure component can be isolated from other high altitude stresses such as temperature, desiccation, and even hypoxia. In addition, hypobaria can be carried to extremes beyond what is possible in terrestrial biomes, and explored as a single variable in the examination of plant responses to novel stress. Previous studies have shown that plants adjust to hypobaric stress by differentially expressing suites of genes in unique combinations that are not equal to the dissected components of hypobaric stress (such as hypoxia and desiccation). Here we examine the organ-specific progression of transcriptional strategies for physiological adaptation to hypobaric stress over time. An abrupt transition from a near-sea level pressure of 97 kPa to only 5 kPa is accompanied by the differential expression of hundreds of genes. However, the transcriptomic reaction to hypobaric conditions lying between these two extremes reveals complex, organ-specific responses that vary over a time course of hypobaric exposure, and that are also not linear with respect to a simple gradient of severity. It is also clear that plants adjust over time such that the gene expression patterns that are initially elicited to cope with hypobaria are mediated as plants adjust their metabolism to this environment. The patterns of genome-wide changes in gene expression across a gradient of atmospheric pressures, and over a time course of several days allows for the development of theories of how plant metabolisms may be adapting to changes in atmospheric pressures.
No associated publication
Age, Specimen part
View SamplesThe polytrauma (PT) murine model has unique transcriptomic responses 2 hrs, 1 day and 3 days after injury. We determined with this clinically relevant model that the increased morbidity in the elderly is secondary to a failure of bone marrow progenitors, blood neutrophils, and bronchoalveolar lavage cells to initiate and complete an 'emergency myelopoietic' response, engendering myeloid cells that fail to clear secondary infection. In addition, the elderly appear unable to effectively resolve their inflammatory response to severe injury.
A Detailed Characterization of the Dysfunctional Immunity and Abnormal Myelopoiesis Induced by Severe Shock and Trauma in the Aged.
Sex, Specimen part, Treatment
View SamplesIn this data set, we reported for the first time that huanglongbing disease (HLB) induces major changes in the expression of global genes in flavedo, vascular and juice vesicle tissues of citrus fruit.
Gene expression in Citrus sinensis fruit tissues harvested from huanglongbing-infected trees: comparison with girdled fruit.
Specimen part
View SamplesMYB activation is proposed to underlie development of adenoid cystic cancer (ACC), an aggressive salivary gland tumor with no effective systemic treatments. To discover druggable targets for ACC, we performed global mRNA/miRNA analyses of 12 ACC with matched normal tissues, and compared these data with 14 mucoepidermoid carcinomas (MEC) and 11 salivary adenocarcinomas (ADC). We detected a unique ACC gene signature of 1160 mRNAs and 22 miRNAs. MYB was the top-scoring gene (18-fold induction), however we observed the same signature in ACC without detectable MYB gene rearrangements. We also found 4 ACC tumors (1 among our 12 cases and 3 from public databases) with negligible MYB expression that retained the same ACC mRNA signature including over-expression of extracellular matrix (ECM) genes. Integration of this signature with somatic mutational analyses suggests that NOTCH1 and RUNX1 participate with MYB to activate ECM elements including the VCAN/HAPLN1 complex. We observed that forced MYB-NFIB expression in human salivary gland cells alters cell morphology and cell adhesion in vitro and depletion of VCAN blocked tumor cell growth of a short-term ACC tumor culture. In summary, we identified a unique ACC signature with parallel MYB-dependent and independent biomarkers and identified VCAN/HAPLN1 complexes as a potential target.
A unifying gene signature for adenoid cystic cancer identifies parallel MYB-dependent and MYB-independent therapeutic targets.
Specimen part, Disease
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