Nuclear receptors (NRs) are ligand-activated transcription factors regulating a large variety of processes involved in reproduction, development, and metabolism. NRs are ideal drug targets. Immortalized cell lines recapitulate NR biology very poorly and primary cultures are laborious and require a constant need for donor material. There is a clear need for development of novel preclinical model systems that better resemble human physiology since technical uncertainty early in drug development is the cause of many preclinical drugs not reaching the clinic. Here, we studied whether organoids, mini-organs derived from the respective tissues stem cells, can serve as a novel (preclinical) model system to study NR biology and targeteability. We characterized mRNA expression profiles of the NR superfamily in mouse liver, ileum, and colon organoids. NR mRNA expression patterns were similar to the respective tissues, indicating their suitability for NR research. Metabolic NRs Fxr, Lxr, Lxr, Ppar, and Ppar were responsive to ligands in an NR-dependent fashion, as demonstrated by regulation of expression and binding to endogenous target genes. Transcriptome analyses of wildtype colonic organoids stimulated with Rosiglitazone showed that lipid metabolism was the highest significant changed function, greatly mimicking the known function of PPARs and Rosiglitazone in vivo. In conclusion, our results demonstrate that organoids constitutes a versatile and promising in vitro system to study NR biology and targeteability.
Characterization of stem cell-derived liver and intestinal organoids as a model system to study nuclear receptor biology.
Treatment
View SamplesTo determine the modulation of gene expression of C57BL/6 and DBA/2 BMDLs in the presence of living intracellular Leishmania amazonensis amastigotes
Distinct transcriptional signatures of bone marrow-derived C57BL/6 and DBA/2 dendritic leucocytes hosting live Leishmania amazonensis amastigotes.
Specimen part
View SamplesIn this data set we include expression data from human CD4+ T cells isolated on day 0, 6, 11 and 24 follow anti-CD3/anti-CD28 magnetic bead stimulation and chimeric antigen receptor transduction.
Identification of chimeric antigen receptors that mediate constitutive or inducible proliferation of T cells.
Specimen part
View SamplesIn mammals, resident dermal macrophages (Ms) are subverted by Leishmania (L.) amazonensis amastigotes as host cells permissive for parasite multiplication. These Leishmania are living within a communal parasitophorous vacuole (PV) and are expected to trigger unique M transcriptional signatures. We performed a transcription profiling of mouse Ms harboring amastigotes to get insights into their reprogramming as host cells for parasite multiplication. BALB/c mouse bone marrow-derived Ms were either loaded or not with four amastigotes on average. Twenty four hours later, when amastigotes multiply, total RNA from M cultures was prepared, amplified and hybridized onto Affymetrix Mouse430_2 GeneChips. The outcome recorded a total of 1,248 probe-sets showing significant differential expression. Comparable fold-change values for a handful of genes were obtained between Affymetrix technology and the more sensitive RTqPCR method. Ingenuity Pathway Analysis software pinpointed the up-regulation of the sterol biosynthesis pathway (P-value = 1.31e-02) involving several genes (1.95 to 4.30 fold-change values), and the modulation of various genes involved in polyamine synthesis and in pro/counter-inflammatory signaling. Our findings suggest that amastigotes exploit the M lipid and polyamine pathways to multiply efficiently, and induce a counter-inflammatory environment to expand their dermis niche.
Transcriptional signatures of BALB/c mouse macrophages housing multiplying Leishmania amazonensis amastigotes.
No sample metadata fields
View SamplesThe Gfi1-Cre mouse is commonly used for conditional hair cell-specific gene deletion/activation in the inner ear. However, we have shown that these mice produce a pattern of recombination that is not strictly limited to hair cells, and that Gfi1cre/+ mice exhibit an early onset progressive hearing loss as compared with their wildtype littermates. Here we performed a transcriptome analysis of Gfi1cre/+ and Gfi1+/+ cochlea to detect potential changes in gene expression that could contribute to their hearing loss phenotype, or that could potentially confound downstream analysis of conditional gene deletion using these mice. Overall design: Trancriptome profiles of P8 cochlear duct from mice of two genotype - Gfi1cre/+ and Gfi+/+ controls - were measured. Gene expression levels were recorded in independent triplicates using polyA-enriched RNA-seq
Gfi1<sup>Cre</sup> mice have early onset progressive hearing loss and induce recombination in numerous inner ear non-hair cells.
Specimen part, Cell line, Subject
View SamplesThis SuperSeries is composed of the SubSeries listed below.
Gene expression profiling in human precision cut liver slices in response to the FXR agonist obeticholic acid.
Sex, Specimen part, Treatment, Subject, Time
View SamplesBackground: The bile acid-activated farnesoid X receptor (FXR) is a nuclear receptor regulating bile acid, glucose and cholesterol homeostasis. Obeticholic acid (OCA; also known as INT-747 or 6-ethyl-chenodeoxycholic acid), a promising drug for the treatment of non-alcoholic steatohepatitis (NASH) and type 2 diabetes, activates FXR. Mouse studies demonstrated that FXR activation by OCA (INT-747) alters hepatic expression of many genes. However, no data are available on the effects of OCA in human liver. Here, we generated gene expression profiles in human precision-cut liver slices (hPCLS) after treatment with OCA.
Gene expression profiling in human precision cut liver slices in response to the FXR agonist obeticholic acid.
Sex, Specimen part, Treatment, Time
View SamplesBackground: The bile acid-activated farnesoid X receptor (FXR) is a nuclear receptor regulating bile acid, glucose and cholesterol homeostasis. Obeticholic acid (OCA; also known as INT-747 or 6-ethyl-chenodeoxycholic acid), a promising drug for the treatment of non-alcoholic steatohepatitis (NASH) and type 2 diabetes, activates FXR. Mouse studies demonstrated that FXR activation by OCA (INT-747) alters hepatic expression of many genes. However, no data are available on the effects of OCA in human liver. Here, we generated gene expression profiles in human precision-cut liver slices (hPCLS) after treatment with OCA.
Gene expression profiling in human precision cut liver slices in response to the FXR agonist obeticholic acid.
Sex, Specimen part, Treatment, Subject, Time
View SamplesTo determine the modulation of gene expression of mouse BMDCs in the presence of living intracellular Leishmania amazonensis amastigotes
Sorting of Leishmania-bearing dendritic cells reveals subtle parasite-induced modulation of host-cell gene expression.
Sex, Age
View SamplesTo determine the modulation of gene expression of mouse BMDCs in the presence of living intracellular Leishmania amazonensis amastigotes at 24 hr post infection.
<i>Leishmania amazonensis</i> Subverts the Transcription Factor Landscape in Dendritic Cells to Avoid Inflammasome Activation and Stall Maturation.
Specimen part, Time
View Samples