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GSE57597
Mus musculus
58 Downloadable Samples
Affymetrix Mouse Gene 2.0 ST Array (mogene20st)
Description
AAV gene therapy has recently been approved for clinical use and shown to be efficacious and safe in a growing number of clinical trials. However, the safety of AAV as a gene therapy has been challenged by a few studies that documented hepatocellular carcinoma (HCC) after AAV gene delivery in mice. The association between AAV and HCC has been difficult to reconcile and is the subject of intense debate because numerous AAV studies have not reported toxicity. Here, we report a comprehensive study of HCC in a large number of mice following therapeutic AAV gene delivery. Using a sensitive high-throughput integration site-capture technique and global expressional analysis, we found that AAV integration into the Rian locus and the over-expression of a proximal gene, Rtl1, were associated with HCC. In addition, we identify a number of genes with differential expression that maybe useful in the study, diagnosis and treatment of HCC. We demonstrate that AAV vector dose, enhancer-promoter selection, and the timing of gene delivery are the defining factors in AAV-mediated insertional mutagenesis. Our results help explain the AAV-mediated genotoxicity previously observed and have important implications for the design of both safer AAV vectors and gene therapy studies.
Publication Title
No associated publication
Sample Metadata Fields
Sex, Specimen part, Disease
View Samples- Mus musculus
- 23 Downloadable Samples
- Affymetrix Mouse Gene 2.0 ST Array (mogene20st)
Description
In two disparate models, we show that rapid revaccination following sublethal gamma radiation exposure rescues memory CD8+ T cell Responses.
Publication Title
Rescue of CD8+ T cell vaccine memory following sublethal γ irradiation.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 21 Downloadable Samples
- Affymetrix Mouse Gene 2.0 ST Array (mogene20st)
Description
An animals ability to cope with or succumb to deleterious effects of chronic psychological stress may be rooted in the brains immune responses manifested in microglial activity. Mice subjected to chronic social defeat (CSD) were categorized as susceptible (CSD-S) or resilient (CSD-R) based on behavioral phenotyping, and their microglial RNAs were isolated and analyzed by global gene expression microarrays. Microglia transcriptome from CSD-S mice was enriched for pathways that describe phases of CNS healing to sterile injury including, inflammation, oxidative stress, debris clearance, and wound resolution. Histochemical experiments confirmed the array predictions: CSD-S microglia showed elevated phagocytosis and oxidative stress, and the brains of CSD-S but not CSD-R or HC mice showed vascular leakage of intravenously injected fluorescent tracers. The results suggest that the inflammatory profile of CSD-S microglia may be precipitated by leakage of blood-born substances into brain parenchyma. We hypothesize that these CNS-centric responses contribute to the stress-susceptible behavioral phenotype.
Publication Title
Decoding microglia responses to psychosocial stress reveals blood-brain barrier breakdown that may drive stress susceptibility.
Sample Metadata Fields
Specimen part
View Samples- Mus musculus
- 19 Downloadable Samples
- Affymetrix Mouse Gene 2.0 ST Array (mogene20st)
Description
The resident skin microbiota plays a fundamental role in the control of skin physiology and growing evidence support the idea that, at this barrier site, both immunity and inflammatory processes are controlled by skin resident microbiota. However, how defined skin microbes influence the skin immune system under both steady state conditions and inflammatory settings remains poorly understood. Obesity has been linked to increased prevalence of skin inflammatory disorders.
Publication Title
No associated publication
Sample Metadata Fields
Specimen part
View Samples- Mus musculus
- 15 Downloadable Samples
- Affymetrix Mouse Gene 2.0 ST Array (mogene20st)
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
Telmisartan Protects a Microglia Cell Line from LPS Injury Beyond AT1 Receptor Blockade or PPARγ Activation.
Sample Metadata Fields
Specimen part, Cell line, Treatment
View Samples- Mus musculus
- 16 Downloadable Samples
- Affymetrix Mouse Gene 2.0 ST Array (mogene20st)
Description
The white adipose tissue represents 15% of healthy mammalian hosts and bridges body organs. In addition to serving as a scaffold for the lymphatic and blood vasculature, this compartment plays a fundamental role in the control of host metabolism. To which extent the adipose tissue also contributes to immune surveillance and long-term protective defense remains largely unknown. Here, we show that under steady state conditions, the white adipose tissue is home to abundant and diverse memory lymphocyte populations. Following infection, the adipose tissue accumulates large numbers of pathogen-specific memory T cells, including tissue-resident (TRM) cells. Memory T cells found in the adipose tissue express a distinct metabolic profile and are characterized by heightened proliferative and effector capacity. As such, adipose tissue from previously infected mice is sufficient to protect from lethal challenge. Local reactivation of adipose tissue memory T cells leads to rapid responses with local impacts on both immune and metabolic pathways, including direct responses by adipocytes. Notably, induction of recall responses within the adipose tissue is associated with the collapse of lipid metabolism in favor of antimicrobial responses. Thus, our results propose that the white adipose tissue, a compartment that interfaces with all body organs, may represent a unique immune compartment, able to provide early warning and potent effector memory responses. Together, these results uncover the adipose tissue as a dominant reservoir of memory T cells endowed with long-term protective functions, positioning this compartment as a potential major contributor of immunological memory.
Publication Title
No associated publication
Sample Metadata Fields
Specimen part
View Samples- Homo sapiens
- 16 Downloadable Samples
- Affymetrix Human Gene 1.0 ST Array (hugene10st)
Description
We have discovered frequent genetic inactivation of the STAG2 gene in diverse human cancers including glioblastoma, Ewing's sarcoma, and melanoma. STAG2 encodes a subunit of the sister chromatid cohesion complex called the "cohesin complex" that is responsible for the cohesion of sister chromatids following DNA replication and is cleaved at the metaphase to anaphase transition to enable chromosome segregation into daughter cells. Interestingly, the cohesin complex has also been implicated as a regulator of chromatin architecture and transcription. To determine the functional significance of STAG2 inactivation in cancer pathogenesis, we used somatic cell gene targeting to correct the endogenous mutations of STAG2 in two aneuploid human glioblastoma cell lines, H4 and 42MGBA. Similarly, somatic cell gene targeting was also used to introduce a nonsense mutation into codon 6 of the endogenous wild-type allele of STAG2 in HCT116 cells, a near-diploid human colorectal cancer cell line with stable karyotype. Expression profiling of these three paired sets of STAG2-proficient and deficient cells demonstrated that STAG2 does not play a global role in transcriptional regulation nor does it recurrently modulate the expression of specific tumor-promoting or suppressing genes.
Publication Title
Mutational inactivation of STAG2 causes aneuploidy in human cancer.
Sample Metadata Fields
Specimen part, Cell line
View Samples- Rattus norvegicus
- 16 Downloadable Samples
- Affymetrix Rat Gene 2.0 ST Array (ragene20st)
Description
Neuronal cultures were treated with candesartan at neuroprotective concentrations followed by excitotoxic glutamate amounts. Candesartan significantly reduced glutamate-induced inflammation. To provide mechanistic insight into the potential targets and pathways that may underlie these benefits, we performed genome wide expression profile analysis and evaluated the data by Ingenuity Pathway Analysis (IPA) and Gene Set Enrichment Analysis (GSEA). We found that the inflammation signal transduction pathways were major components of the neuronal response to glutamate excitotoxicity, and that candesartan significantly ameliorated glutamate-induced alterations in gene expression. Further analysis showed significant associations of these genes with two independent published networks identified by microarray analysis of hippocampal samples obtained post-mortem from brains of patients diagnosed with AD .
Publication Title
An integrative genome-wide transcriptome reveals that candesartan is neuroprotective and a candidate therapeutic for Alzheimer's disease.
Sample Metadata Fields
Specimen part, Treatment
View Samples- Mus musculus
- 16 Downloadable Samples
- Affymetrix Mouse Gene 1.0 ST Array (mogene10st)
Description
Nonalcoholic fatty liver disease (NAFLD) is the most common form of liver disease and a leading cause of liver transplantation in the United Sates. Hedgehog (Hh) signaling has been implicated in liver lipid metabolism and the early stages of NAFLD; however, its precise role remains unclear. We examined the prevalence of NAFLD in patients with overt or microform holoprosencephaly (HPE), a disorder associated with germline mutations disrupting Hh signaling. To test the hypothesis that Hh signaling attenuation predisposes to liver steatosis, we subjected Gli2 heterozygous null (Gli2+/-) mice to two unique dietary models of fatty liver. Compared to the general population, the prevalence of NAFLD was significantly higher in the HPE cohort independent of obesity, especially among younger individuals. Gli2 heterozygosity caused increased weight gain and liver steatosis on a high fat diet, and increased liver steatosis in the absence of weight gain on a methionine and choline deficient diet. Increased liver steatosis in Gli2+/- mice was associated with decreased expression of pro-fibrotic and pro-inflammatory genes and increased expression of PPAR, a potent anti-fibrogenic and anti-inflammatory regulator. In addition, tumor suppressors p53 and p16INK4 were found to be downregulated in the Gli2+/- mice. Our results indicate that germline mutations affecting Hh signaling predispose to NAFLD with reduced or absent fibrosis, and might increase the risk of hepatocellular carcinoma.
Publication Title
Human germline hedgehog pathway mutations predispose to fatty liver.
Sample Metadata Fields
Specimen part
View Samples- Homo sapiens
- 15 Downloadable Samples
- Affymetrix Human Gene 1.0 ST Array (hugene10st)
Description
Intercellular communication is critical for integrating complex signals in multicellular eukaryotes. Vascular endothelial cells and T lymphocytes closely interact during the recirculation and trans-endothelial migration of T cells. In addition to direct cell-cell contact, we show that T cell derived extracellular vesicles can interact with endothelial cells and modulate their cellular functions. Thrombospondin-1 and its receptor CD47 are expressed on exosomes/ectosomes derived from T cells, and these extracellular vesicles are internalized and modulate signaling in both T cells and endothelial cells. Extracellular vesicles released from cells expressing or lacking CD47 differentially regulate activation of T cells induced by engaging the T cell receptor. Similarly, T cell-derived extracellular vesicles modulate endothelial cell responses to vascular endothelial growth factor and tube formation in a CD47-dependent manner. Uptake of T cell derived extracellular vesicles by recipient endothelial cells globally alters gene expression in a CD47-dependent manner. CD47 also regulates the mRNA content of extracellular vesicles in a manner consistent with some of the resulting alterations in target endothelial cell gene expression. Therefore, the thrombospondin-1 receptor CD47 directly or indirectly regulates intercellular communication mediated by the transfer of extracellular vesicles between vascular cells.
Publication Title
CD47-dependent immunomodulatory and angiogenic activities of extracellular vesicles produced by T cells.
Sample Metadata Fields
Specimen part, Cell line, Treatment
View Samples