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SRP111108
Mus musculus
18 Downloadable Samples
Illumina HiSeq 4000
Description
Immune checkpoint blockade is able to achieve durable responses in a subset of patients, however we lack a satisfying comprehension of the underlying mechanisms of anti-CTLA-4 and anti-PD-1 induced tumor rejection. To address these issues we utilized mass cytometry to comprehensively profile the effects of checkpoint blockade on tumor immune infiltrates in human melanoma and murine tumor models. These analyses reveal a spectrum of tumor infiltrating T cell populations that are highly similar between tumor models and indicate that checkpoint blockade targets only specific subsets of tumor infiltrating T cell populations. Anti-PD-1 predominantly induces the expansion of specific tumor infiltrating exhausted-like CD8 T cell subsets. In contrast, anti-CTLA-4 induces the expansion of an ICOS+ Th1-like CD4 effector population in addition to engaging specific subsets of exhausted-like CD8 T cells. Thus, our findings indicate that anti-CTLA-4 and anti-PD-1 checkpoint blockade induced immune responses are driven by distinct cellular mechanisms. Overall design: RNA profiles of a subset of tumor infiltrating T cell populations in anti-PD-1, anti-CTLA-r and control mice were generated by RNA sequencing, using Illumina HiSeq 4000. Mouse mutation background was assessed by whole exome sequencing data
Publication Title
Distinct Cellular Mechanisms Underlie Anti-CTLA-4 and Anti-PD-1 Checkpoint Blockade.
Sample Metadata Fields
Specimen part, Cell line, Subject
View Samples- Mus musculus
- 29 Downloadable Samples
- Illumina HiSeq 2000
Description
Regulator of G protein signaling z1 (RGSz1), a member of the RGS family of proteins, is present in several networks expressing mu opioid receptors (MOPR). By using genetic mouse models for global or brain region-targeted manipulations of RGSz1 expression, we demonstrate that the suppression of RGSz1 function increases the analgesic efficacy of MOPR agonists in male and female mice and delays the development of morphine tolerance while decreasing the sensitivity to rewarding and locomotor activating effects. Using biochemical assays and next-generation RNA sequencing, we identified a key role of RGSz1 in the periaqueductal gray (PAG) in morphine tolerance. Chronic morphine administration promotes RGSz1 activity in the PAG, which in turn modulates transcription mediated by the Wnt/ß-catenin signaling pathway to promote analgesic tolerance to morphine. Conversely, the suppression of RGSz1 function stabilizes Axin2-Gaz complexes near the membrane and promotes ß-catenin activation, thereby delaying the development of analgesic tolerance. These data show that the regulation of RGS complexes, particularly those involving RGSz1-Gaz, represents a promising target for optimizing the analgesic actions of opioids without increasing the risk of dependence or addiction. Overall design: Understanding the impact of morphine tolerance and the influence of RGSz1 on gene expression in the PAG
Publication Title
Suppression of RGSz1 function optimizes the actions of opioid analgesics by mechanisms that involve the Wnt/β-catenin pathway.
Sample Metadata Fields
Sex, Specimen part, Treatment, Subject
View Samples- Homo sapiens
- 24 Downloadable Samples
- Illumina HiSeq 2000
Description
Background: Arrhythmogenic cardiomyopathy (ACM) is a genetic autosomal disease characterized by abnormal cell-cell adhesion, cardiomyocyte death, progressive fibro-adipose replacement of the myocardium, arrhythmias and sudden death. Several different cell types contribute to the pathogenesis of ACM, including, as recently described, cardiac stromal cells (CStCs). In the present study, we aim to identify ACM-specific expression profiles of human CStCs derived from endomyocardial biopsies of ACM patients and healthy individuals employing TaqMan Low Density Arrays for miRNA expression profiling, and high throughput sequencing for gene expression quantification. Results: We identified 5 miRNAs and 272 genes as significantly differentially expressed. Both the differentially expressed genes as well as the target genes of the ACM-specific miRNAs were found to be enriched in cell adhesion related biological processes. Functional similarity and protein interaction based network analyses performed on the identified deregulated genes, miRNA targets and known ACM-causative genes revealed clusters of highly related genes involved in cell adhesion, extracellular matrix organization, lipid transport and ephrin receptor signaling. Conclusions: We determined for the first time the coding and non-coding transcriptome characteristic of ACM cardiac stromal cells, finding evidence for a potential contribution of miRNAs to ACM pathogenesis or phenotype maintenance. Besides known pathways, we identified also deregulation of genes encoding ephrin receptors and ephrins, thus suggesting a potential involvement of Eph-ephrin signaling in CStCs from ACM hearts. Overall design: Expression profiles of cardiac stromal cells from 3 ACM patients were compared against those of cardiac stromal cells from 3 healthy individuals.
Publication Title
The arrhythmogenic cardiomyopathy-specific coding and non-coding transcriptome in human cardiac stromal cells.
Sample Metadata Fields
Sex, Disease, Subject
View Samples- Mus musculus
- 12 Downloadable Samples
Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
To better understand the mechanistic basis of aging and its relationship with retinal degeneration, we examined gene expression changes in aging rod photoreceptors. Rod photoreceptor cell death is a feature of normal retinal aging and is accelerated in many retinal degenerative diseases, including AMD, the leading cause of untreatable adult blindness in the United States and other western countries. To our knowledge, the examination of age-related gene expression changes in a specific neuronal cell-type is novel, and it has allowed us to identify significant age-related changes with better resolution than is possible with whole retina samples. We used flow cytometry and a transgenic mouse with GFP-tagged rod photoreceptors to purify this specific cell population, and gene expression changes were evaluated at three time points using microarrays and quantitative RT-PCR. Our results suggest that aging is progressive, beginning even in young adult mice. Although rod photoreceptors are highly specialized neurons, our analyses revealed changes in consensus pathways of aging, including oxidative phosphorylation and stress responses affecting transcription and inflammation. In addition, we identified stress response processes that may be especially relevant for the aging retina and retinal diseases, such as angiogenesis and nuclear receptor signaling pathways that affect retinoid and lipid metabolism.
Publication Title
Distinct signature of altered homeostasis in aging rod photoreceptors: implications for retinal diseases.
Sample Metadata Fields
Age, Specimen part
View Samples- Homo sapiens
- 6 Downloadable Samples
- Illumina HiSeq 2500
Description
We discuss the use of pluripotent stem cell lines carrying fluorescent reporters driven by retinal promoters to derive three-dimensional (3-D) retina in culture and how this system can be exploited for elucidating human retinal biology, creating disease models in a dish, and designing targeted drug screens for retinal and macular degeneration. Furthermore, we realize that stem cell investigations are labor-intensive and require extensive resources. To expedite scientific discovery by sharing of resources and to avoid duplication of efforts, we propose the formation of a Retinal Stem Cell Consortium. In the field of vision, such collaborative approaches have been enormously successful in elucidating genetic susceptibility associated with age-related macular degeneration. Overall design: CRX+ flow sorted cells from human retina derived organoids were collected at 6 time points during differentiation (day (D) 37, 48, 67, 90, 134, 220).
Publication Title
Treatment Paradigms for Retinal and Macular Diseases Using 3-D Retina Cultures Derived From Human Reporter Pluripotent Stem Cell Lines.
Sample Metadata Fields
Specimen part, Subject
View Samples- Mus musculus
- 29 Downloadable Samples
- Illumina Genome Analyzer IIx
Description
We postulate here that the two singular characteristics of the mitochondrial oxidative phosphorylation system—the integration of three potentially antagonistic functions in the same structure and the double genetic origin of the components that assemble together in these molecular machines—make the evolution of an optimal system impossible. As a consequence the system is intrinsically mismatched and has to be continuously monitored, Adjusted and regulated in order to achieve the necessary and variable performance. Systematic transcriptomic, Metabolomic and biochemical evaluation of animals with identical nuclear DNA but different mtDNA haplotype strongly support the existence of intrinsic mismatch and reveals profound lifelong metabolic consequences on reactive oxygen species generation, Insulin signaling, Tendency towards obesity, And healthy ageing parameters, Including telomere atresia Overall design: Transcriptome analysis of conplastic mice versus WT mice in Liver and Heart tissues Conplastic strains were obtained after 10 generations of backcrossing to create a new line harboring the nuclear genome of one strain and the mtDNA of another (C57BL/6 and NZB were purchased from Harlan Laboratories).
Publication Title
Mitochondrial and nuclear DNA matching shapes metabolism and healthy ageing.
Sample Metadata Fields
No sample metadata fields
View Samples- Triticum aestivum
- 41 Downloadable Samples
- Affymetrix Wheat Genome Array (wheat)
Description
Different wheat cultivars may be classified as either winter or spring varieties depending on whether they require exposure to an extended period of cold in order to become competent to flower. Using a growth regime that mimics the conditions that occur during a typical winter in Britain, we wished to survey the genes that are involved in phase transition as well as those involved in cold-acclimation.
Publication Title
Cold- and light-induced changes in the transcriptome of wheat leading to phase transition from vegetative to reproductive growth.
Sample Metadata Fields
No sample metadata fields
View Samples- Homo sapiens
- 7 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Bacillus anthracis is a gram-positive, aerobic, spore-forming, rod-shaped bacterium which has recently been used as an agent of bioterrorism. Because there is a significant delay between the initial contact of the spore with the host and clinical evidence of disease, there appears to be temporary containment of the pathogen by the innate immune system. Contact with the human alveolar macrophage (HAM) plays a key role in the innate immune response to B. anthracis spores. Therefore, the early macrophage response to anthrax exposure is important in understanding the pathogenesis of this disease. The majority of genes modulated by spores were upregulated, and a lesser number were downregulated. The data was subjected to Ingenuity Pathway analysis, the Database for Annotation, Visualization and Integrated Discovery (DAVID) analysis, and the Promoter Analysis and Interaction Network Toolset (PAINT). Among the upregulated genes, we identified a group of chemokine ligands, apoptosis genes and, interestingly, keratin filament genes. Central hubs regulating the activated genes were TNF-alpha, NF-B and their ligands/receptors. Other activated genes included IL-1alpha and IL-18. RNA for these, and several additional cytokines including IL-6, IL-1gamma, IP-10 and GM-CSF, were differentially expressed from 1.6- to 27-fold. The microarray cytokine data is consistent with our previously published findings which demonstrated that there was 4- to 43-fold induction of these cytokines at the transcriptional and translational levels as determined by RNase protection assays and ELISA. The PAINT analysis revealed that the majority of the genes affected by spores contain the binding site for c-Rel, a member of the NF-B family of transcription factors. Other transcription regulatory elements contained in many of the upregulated genes were c-Myb, CP2, Barbie Box, E2F and CRE-BP1. This study is the first detailed microarray analysis to describe the HAM response to B. anthracis.
Publication Title
Gene expression profiling of human alveolar macrophages infected by B. anthracis spores demonstrates TNF-alpha and NF-kappab are key components of the innate immune response to the pathogen.
Sample Metadata Fields
No sample metadata fields
View Samples- Gallus gallus
- 24 Downloadable Samples
- Affymetrix Chicken Genome Array (chicken)
Description
In the present study, we examined the hepatic transcriptome of chickens during the peri-hatch periodor the metabolic jump from chorioallantoic (embryo) to pulmonary (hatchling) respiration. Although our major interest was comparison of differentially-expressed genes between embryos and hatchlings, we made pairwise contrasts across six developmental ages. We collected the liver from four embryos at three ages (e16, e18 and e20) and four hatchling chicks at three ages (1, 3 and 9 days) post hatching. Liver samples (N=24) were used for extraction of total RNA which was then used for hybridization to 24 Affymetrix Chicken Genome Arrays. Ingenuity Pathways Analysis was used for functional annotation and mapping of differentially expressed (FDR0.05) genes to canonical pathways and gene interaction networks. We identified 1274 hepatic genes that were differentially expressed between embryos and hatchling chicks and of these, 284 genes are involved in lipid metabolism. The three most abundant found in liver of embryos were (MOGAT1, DIO3 and PDK4), whereas THRSP, FASN and DIO2 were greatly expressed in liver of hatchlings. Two functionally-distinct clusters of hepatic genes have emerged from our time-course transcriptional scans in the peri-hatch chicken. Cluster A genes are largely lipolytic with higher expression in the embryo, while Cluster B genes are mainly lipogenic and thermogenic with greater expression in liver of hatchlings. The present study describes the innate chorography of transcriptional responses of liver to the abrupt metabolic switch from aquatic ectothermy (embryos) to free-living endothermy (hatchling chicks).
Publication Title
Transcriptional profiling of liver during the critical embryo-to-hatchling transition period in the chicken (Gallus gallus).
Sample Metadata Fields
Sex, Specimen part
View Samples- Homo sapiens
- 24 Downloadable Samples
- Illumina HiSeq 2500
Description
To understand the nature of glucocorticoids targeting non-immune cell function, we generate RNA sequencing data from 3 human podocyte cell lines derived from 3 kidney transplant donors and identify the genes that are significantly regulated in dexamethasone-treated podocytes compared to vehicle-treated cells.Our results represent a significant step forward in the genome-wide characterization of the molecular effects of glucocorticoids on human podocytes. The resource generated in this study is important for understanding the targeting of non-immune cell function by glucocorticoids and also for designing more specific podocyte-targeted agents for MCN therapy. Overall design: Transcriptome profiles of human podocytes treated with vehicle and dexamethasone were generated by RNA-sequencing using Illumina HiSeq 2500
Publication Title
RNA sequencing analysis of human podocytes reveals glucocorticoid regulated gene networks targeting non-immune pathways.
Sample Metadata Fields
Specimen part, Subject
View Samples