Filters
Technology
Platform
Homo sapiens, Rattus norvegicus
2 Downloadable Samples
Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
MicroRNAs (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.
Publication Title
Striatal microRNA controls cocaine intake through CREB signalling.
Sample Metadata Fields
Sex, Specimen part, Cell line
View Samples
GSE10377- Mus musculus
- 5 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
Background
Publication Title
Expression quantitative trait loci mapping identifies new genetic models of glutathione S-transferase variation.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 4 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
Both 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.
Publication Title
Genetic regulation of behavioral and neuronal responses to fluoxetine.
Sample Metadata Fields
Sex, Treatment
View Samples- Homo sapiens
- 1 Downloadable Sample
- Affymetrix Human Gene 2.0 ST Array (hugene20st)
Description
In 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.
Publication Title
No associated publication
Sample Metadata Fields
Specimen part
View Samples- Homo sapiens
- 48 Downloadable Samples
- Illumina HumanHT-12 V3.0 expression beadchip
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
Recurrent variations in DNA methylation in human pluripotent stem cells and their differentiated derivatives.
Sample Metadata Fields
Sex, Specimen part, Disease, Cell line, Subject
View Samples- Homo sapiens
- 656 Downloadable Samples
- Affymetrix HT HG-U133+ PM Array Plate (hthgu133pluspm)
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
Development and clinical validity of a novel blood-based molecular biomarker for subclinical acute rejection following kidney transplant.
Sample Metadata Fields
Specimen part
View Samples- Homo sapiens
- 529 Downloadable Samples
- Affymetrix HT HG-U133+ PM Array Plate (hthgu133pluspm)
Description
Sub-clinical acute rejection (subAR) in kidney transplant recipients (KTR) leads to chronic rejection and graft loss. Non-invasive biomarkers are needed to detect subAR. 307 KTR were enrolled into a multi-center observational study. Precise clinical phenotypes (CP) were used to define subAR. Differential gene expression (DGE) data from peripheral blood samples paired with surveillance biopsies were used to train a Random Forests (RF) model to develop a gene expression profile (GEP) for subAR. A separate cohort of paired samples was used to validate the GEP. Clinical endpoints and gene pathway mapping were used to assess clinical validity and biologic relevance. DGE data from 530 samples (130 subAR) collected from 250 KTR yielded a RF model: AUC 0.85; 0.84 after internal validation with bootstrap resampling. We selected a predicted probability threshold favoring specificity and NPV (87% and 88%) over sensitivity and PPV (64% and 61%, respectively). We tested the locked model/threshold on a separate cohort of 138 KTR undergoing surveillance biopsies at our institution (rejection 42; no rejection 96): NPV 78%; PPV 51%; AUC 0.66. Both the CP and GEP of subAR within the first 12 months following transplantation were independently associated with worse graft outcomes at 24 months, including de novo donor-specific antibody (DSA). Serial GEP tracked with response to treatment of subAR. DGE data from both cohorts mapped to gene pathways indicative of allograft rejection.
Publication Title
Development and clinical validity of a novel blood-based molecular biomarker for subclinical acute rejection following kidney transplant.
Sample Metadata Fields
Specimen part
View Samples- Homo sapiens
- 308 Downloadable Samples
- Affymetrix Human Gene 1.1 ST Array (hugene11st)
Description
Early diagnosis of transthyretin (TTR) amyloid diseases remains challenging because of variable disease penetrance. Currently, patients must have an amyloid positive tissue biopsy to be eligible for disease modifying therapies. Early diagnosis is often difficult because the patient exhibits apparent symptoms of polyneuropathy or cardiomyopathy, but has a negative amyloid biopsy. Thus, there is a pressing need for more objective, quantitative diagnostics and biomarkers of TTR-aggregation-associated polyneuropathy and cardiomyopathy. This is especially true in the context of clinical trials demonstrating significant disease modifying effects, e.g. when the TTR tetramer stabilizer tafamidis was administered to familial amyloid polyneuropathy (FAP) patients early in the disease course. When asked if the findings of the tafamidis registration trial were sufficiently robust to provide substantial evidence of efficacy for a surrogate endpoint that is reasonably likely to predict a clinical benefit the advisory committee said yes, but the FDA rejected the tetramer stabilization surrogate biomarker required for orphan tafamidis approvalhence, acceptable biomarkers are badly needed. Herein, we explored whether peripheral blood cell mRNA expression profiles could differentiate symptomatic from asymptomatic V30M FAP patients, and if such a profile would normalize upon tafamidis treatment. We demonstrate that blood cell gene expression patterns reveal sex-independent as well as male and female specific inflammatory signatures in symptomatic FAP patients, but not in asymptomatic carriers, that normalize in FAP patients 6 months after tafamidis treatment. Thus these signatures have potential both as an early diagnostic and as a surrogate biomarker for measuring response to treatment in FAP patients.
Publication Title
Peripheral Blood Cell Gene Expression Diagnostic for Identifying Symptomatic Transthyretin Amyloidosis Patients: Male and Female Specific Signatures.
Sample Metadata Fields
Age, Specimen part
View Samples- Homo sapiens
- 273 Downloadable Samples
- Affymetrix HT HG-U133+ PM Array Plate (hthgu133pluspm)
Description
Rationale: Interstitial fibrosis and tubular atrophy (IFTA) is found in ~25% of 1-year biopsies post-transplant(1, 2). It correlates with decreased graft survival when histological evidence of inflammation is present.(3-5) Identifying the etiology of IFTA is important because longterm graft survival has not changed as expected given improved therapies and a dramatically reduced incidence of acute rejection.(6-8) Methods: Gene expression profiles of 234 samples were obtained with matching clinical and outcome data (7 transplant centers). 81 IFTA samples were divided into subphenotypes by the degree of inflammation on histology: IFTA with acute rejection (AR), IFTA with inflammation and IFTA without inflammation. Samples with AR (n=54) and normally functioning transplants (TX; n=99) were used in comparisons. Conclusions: Gene expression profiling of all IFTA phenotypes were strongly enriched for cAR gene dysregulation pathways, including IFTA samples without histological evidence of inflammation. Thus, by molecular profiling we demonstrate that most IFTA samples have ongoing immune-mediated injury or chronic rejection that is more sensitively detected by gene expression profiling. We also found that the relative expression of AR-affiliated genes correlated with future graft loss in IFTA samples without inflammation. We conclude that undetected and/or undertreated immune rejection is leading to IFTA and graft failure.
Publication Title
Gene Expression in Biopsies of Acute Rejection and Interstitial Fibrosis/Tubular Atrophy Reveals Highly Shared Mechanisms That Correlate With Worse Long-Term Outcomes.
Sample Metadata Fields
Specimen part, Disease, Disease stage
View Samples- Homo sapiens
- 48 Downloadable Samples
- Illumina HumanHT-12 V3.0 expression beadchip
Description
Human pluripotent stem cells (hPSCs) are potential sources of cells for modeling disease and development, drug discovery, and regenerative medicine. However, it is important to identify factors that may impact the utility of hPSCs for these applications. In an unbiased analysis of 205 hPSC and 130 somatic samples, we identified hPSC-specific epigenetic and transcriptional aberrations in genes subject to X chromosome inactivation (XCI) and genomic imprinting, which were not corrected during directed differentiation. We also found that specific tissue types were distinguished by unique patterns of DNA hypomethylation, which were recapitulated by DNA demethylation during in vitro directed differentiation. Our results suggest that verification of baseline epigenetic status is critical for hPSC-based disease models in which the observed phenotype depends on proper XCI or imprinting, and that tissue-specific DNA methylation patterns can be accurately modeled during directed differentiation of hPSCs, even in the presence of variations in XCI or imprinting.
Publication Title
Recurrent variations in DNA methylation in human pluripotent stem cells and their differentiated derivatives.
Sample Metadata Fields
Sex, Specimen part, Cell line, Subject
View Samples