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Mus musculus
8 Downloadable Samples
Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
Study on gene expression in multifunctional protein 2 deficient mice. Liver samples of two days old mice in normal conditions are used. In total 8 arrays were hybridized corresponding to 4 KO mice and 4 WT mice Results: Cholesterol synthesis is induced and ppar alpha targets also differentially expressed between KO and WT.
Publication Title
Coordinate induction of PPAR alpha and SREBP2 in multifunctional protein 2 deficient mice.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 71 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
HDAC4 reduction: a novel therapeutic strategy to target cytoplasmic huntingtin and ameliorate neurodegeneration.
Sample Metadata Fields
Sex, Age, Specimen part
View Samples- Mus musculus
- 37 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
Histone deacetylase (HDAC) 4 is a transcriptional repressor that contains a glutamine rich domain. We hypothesised that it may be involved in the molecular pathogenesis of Huntingtons disease (HD), a protein folding neurodegenerative disorder caused by an aggregation-prone polyglutamine expansion and transcriptional dysregulation. We found that HDAC4 interacts with huntingtin in a polyglutamine-length dependent manner and co-localises with cytoplasmic inclusions. We show that HDAC4 reduction delayed cytoplasmic aggregate formation, restored Bdnf transcript levels and rescued neuronal and cortico-striatal synaptic function in HD mouse models. This was accompanied by an improvement in motor co-ordination, neurological phenotypes and increased lifespan. Surprisingly, HDAC4 reduction had no effect on global transcriptional dysfunction and did not modulate nuclear huntingtin aggregation. Our results define a crucial role for cytoplasmic aggregation in the molecular pathology of HD. HDAC4 reduction presents a novel strategy for targeting huntingtin aggregation which may be amenable to small molecule therapeutics.
Publication Title
HDAC4 reduction: a novel therapeutic strategy to target cytoplasmic huntingtin and ameliorate neurodegeneration.
Sample Metadata Fields
Sex, Age, Specimen part
View Samples- Mus musculus
- 34 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
Histone deacetylase (HDAC) 4 is a transcriptional repressor that contains a glutamine rich domain. We hypothesised that it may be involved in the molecular pathogenesis of Huntingtons disease (HD), a protein folding neurodegenerative disorder caused by an aggregation-prone polyglutamine expansion and transcriptional dysregulation. We found that HDAC4 interacts with huntingtin in a polyglutamine-length dependent manner and co-localises with cytoplasmic inclusions. We show that HDAC4 reduction delayed cytoplasmic aggregate formation, restored Bdnf transcript levels and rescued neuronal and cortico-striatal synaptic function in HD mouse models. This was accompanied by an improvement in motor co-ordination, neurological phenotypes and increased lifespan. Surprisingly, HDAC4 reduction had no effect on global transcriptional dysfunction and did not modulate nuclear huntingtin aggregation. Our results define a crucial role for cytoplasmic aggregation in the molecular pathology of HD. HDAC4 reduction presents a novel strategy for targeting huntingtin aggregation which may be amenable to small molecule therapeutics.
Publication Title
HDAC4 reduction: a novel therapeutic strategy to target cytoplasmic huntingtin and ameliorate neurodegeneration.
Sample Metadata Fields
Sex, Age, Specimen part
View Samples
SRP001455- Caenorhabditis elegans
- 20 Downloadable Samples
Illumina Genome Analyzer
Description
High throughput sequencing to derive function of cde-1 in endogenous RNAi in C. elegans Overall design: Small RNAs were cloned from C. elegans adults, following removal of tri-phosphate groups from 5'' end. Sequencing was performed using the Illumina 1G platform.
Publication Title
CDE-1 affects chromosome segregation through uridylation of CSR-1-bound siRNAs.
Sample Metadata Fields
Specimen part, Subject
View Samples- Homo sapiens
- 8 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
The insulin-like growth factor (IGF) system consists of two ligands (IGF-I and IGF-II), which both signal through type I IGF receptor (IGF-IR) to stimulate proliferation and inhibit apoptosis, with activity contributing to malignant growth of many types of human cancers. We have developed a humanized, affinity-matured anti-human IGF-IR monoclonal antibody (h10H5), which binds with high affinity and specificity to the extracellular domain. h10H5 inhibits IGF-IR-mediated signaling by blocking IGF-I and IGF-IIbinding and by inducing cell surface receptor down-regulation via internalization and degradation. In vitro, h10H5 exhibits anti-proliferative effects on cancer cell lines. In vivo, h10H5 demonstrates single-agent anti-tumor efficacy in human SK-N-AS neuroblastoma and SW527 breast cancer xenograft models, and even greater efficacy in combination with the chemotherapeutic agent Docetaxel or an anti-VEGF antibody. Anti-tumor activity of h10H5 is associated with decreased AKT activation and glucose uptake, and a 316-gene transcription profile with significant changes involving DNA metabolic and cell cycle machineries. These data support the clinical testing of h10H5 as a biotherapeutic for IGF-IR-dependent human tumors.
Publication Title
Antixenograft tumor activity of a humanized anti-insulin-like growth factor-I receptor monoclonal antibody is associated with decreased AKT activation and glucose uptake.
Sample Metadata Fields
No sample metadata fields
View Samples- Caenorhabditis elegans
- 3 Downloadable Samples
- Illumina Genome Analyzer II
Description
High-throughput pyrosequencing of endogenous small RNAs from CSR-1 IP complexes and csr-1(tm892) and ego-1(om97) mutants with corresponding controls. RNAi-related pathways regulate diverse processes, from developmental timing to transposon silencing. Here, we show that in C. elegans the Argonaute CSR-1, the RNA-dependent RNA polymerase EGO-1, the Dicer-related helicase DRH-3, and the Tudor-domain protein EKL-1 localize to chromosomes and are required for proper chromosome segregation. In the absence of these factors chromosomes fail to align at the metaphase plate and kinetochores do not orient to opposing spindle poles. Surprisingly, the CSR-1 interacting small RNAs (22G-RNAs) are antisense to thousands of germline-expressed protein-coding genes. Nematodes assemble holocentric chromosomes in which continuous kinetochores must span the expressed domains of the genome. We show that CSR-1 interacts with chromatin at target loci, but does not down-regulate target mRNA or protein levels. Instead, our findings support a model in which CSR-1 complexes target protein-coding domains to promote their proper organization within the holocentric chromosomes of C. elegans. Overall design: 5 samples examined. Small RNAs that co-immunopercipitate with CSR-1 protein and input sample. Small RNAs from csr-1(tm892) and ego-1(om97) mutants and corresponding congenic wild type strain.
Publication Title
The Argonaute CSR-1 and its 22G-RNA cofactors are required for holocentric chromosome segregation.
Sample Metadata Fields
Cell line, Subject
View Samples- Mus musculus
- 36 Downloadable Samples
- Affymetrix Mouse Gene 1.0 ST Array (mogene10st)
Description
MYC is a pleiotropic transcription factor that regulates numerous pathways and whose deregulation promotes cancer. Myc+/- mice have extended lifespan relative to their wild type littermates. To better understand the effects of the Myc+/- genotype on cellular processes, microarrays were performed on young (5 month) and old (24 month) Myc+/- and WT males in liver, skeletal muscle, and adipose tissues.
Publication Title
Reduced expression of MYC increases longevity and enhances healthspan.
Sample Metadata Fields
Sex, Age, Specimen part
View Samples- Mus musculus
- 11 Downloadable Samples
- Affymetrix Mouse Gene 2.0 ST Array (mogene20st)
Description
We previously showed that severe liver diseases are characterized by expansion of liver progenitor cells (LPC), which correlates with disease severity. However, the origin and role of LPC in liver physiology and in the hepatic response to injury remains a contentious topic. We have now used genetic lineage tracing of Hnf1-expressing biliary duct cells to assess their contribution to LPC expansion and hepatocyte generation during normal liver homeostasis, and following different types of liver injury. We found that ductular reaction cells in human cirrhotic livers express HNF1. However, HNF1 expression was not present in newly generated EpCAM-positive hepatocytes. Using a tamoxifen-inducible Hnf1CreER/R26RYFP/LacZ mouse, we show that there is no contribution of the biliary epithelium to hepatocyte turnover during liver homeostasis in healthy mice. Moreover, after loss of liver mass, Hnf1+ LPC did not contribute to hepatocyte regeneration. We also assessed the contribution of Hnf1+ cells following acute and repeated liver injury. All animal models showed expansion of LPC, as assessed by immunostaining and gene expression profile of sorted YFP-positive cells. A contribution of Hnf1+ LPC to hepatocyte generation was not detected in animal models of liver injury with preserved hepatocyte regenerative potential such as acute acetaminophen, carbon tetrachloride injury, or chronic diethoxycarbonyl-1,4-dihydro-collidin (DDC)-diet. However, in mice fed with choline-deficient ethionine-supplemented (CDE)-diet, which causes profound hepatocyte damage and arrest, a small number of hepatocytes were derived from Hnf1+ cells. Conclusion: Hnf1+ cells do not participate in hepatocyte turnover in the healthy liver or during liver regeneration after partial hepatectomy. After liver injury, LPC arise from the biliary duct epithelium, which gives rise to a limited number of hepatocytes only when hepatocyte regeneration is compromised.
Publication Title
The biliary epithelium gives rise to liver progenitor cells.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 24 Downloadable Samples
- Illumina HiSeq 2000
Description
The heat shock response (HSR) is a mechanism to cope with proteotoxic stress by inducing the expression of molecular chaperones and other heat shock response genes. The HSR is evolutionarily well conserved and has been widely studied in bacteria, cell lines and lower eukaryotic model organisms. However, mechanistic insights into the HSR in higher eukaryotes, in particular in mammals, are limited. We have developed an in vivo heat shock protocol to analyze the HSR in mice and dissected heat shock factor 1 (HSF1)-dependent and -independent pathways. Whilst the induction of proteostasis-related genes was dependent on HSF1, the regulation of circadian function related genes, indicating that the circadian clock oscillators have been reset, was independent of its presence. Furthermore, we demonstrate that the in vivo HSR is impaired in mouse models of Huntington's disease but we were unable to corroborate the general repression of transcription after a heat shock found in lower eukaryotes. Overall design: RNA-Seq was performed on mRNA isolated from quadriceps femoris muscle of 24 mice. These mice were of wild type, R6/2, and Hsf1-/- genotypes. Two mice of each genotype were tested in four conditions: (1) heat shock, (2) control heat shock, (3) HSP90 inhibition (NVP-HSP990), and (4) HSP90 inhibition vehicle.
Publication Title
HSF1-dependent and -independent regulation of the mammalian in vivo heat shock response and its impairment in Huntington's disease mouse models.
Sample Metadata Fields
Age, Specimen part, Treatment, Subject
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