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Mus musculus
4 Downloadable Samples
Description
Ocular immune privilege (IP) limits immune surveillance of intraocular tumors as certain immunogenic tumor cell lines (P815, E.G7-OVA) that are rejected when transplanted in the skin grow progressively when placed in the anterior chamber (a.c.) of the eye. As splenectomy (SPLNX) is known to terminate ocular IP, we characterized immune mechanisms responsible for spontaneous rejection of intraocular tumors in SPLNX mice as a first step toward identifying how to restore tumoricidal activity within the eye. Microarray data showed a 3-fold increase in interferon (IFN)- and a 2.7-fold increase in Fas ligand (FasL). There was a robust increase in transcripts (127 of 408 surveyed) from interferon (IFN)-stimulated genes and a marked decrease (in 40 of 192 surveyed) in the expression of cell-cycle-associated genes. Non-microarray data confirmed that IFN, FasL and CD8+ T cells but not perforin or TNF were required for elimination of intraocular E.G7-OVA tumors that culminated in destruction of the eye (ocular phthsis). IFN and FasL did not target tumor cells directly as the majority of SPLNX IFNR1-/- mice and Fas-defective lpr mice failed to eliminate ocular E.G7-OVA tumors that expressed Fas and IFNR1. Bone marrow chimeras showed that immune cell expression of IFNR1 and Fas was critical and that SPLNX increased the frequency of activated macrophages within ocular tumors in an IFN- and Fas/FasL-dependent manner. Rejection of intraocular tumors was associated with increased ocular mRNA expression of several inflammatory genes including FasL, NOS2, CXCL2 and T-bet. Our data support a model in which IFN- and Fas/FasL-dependent activation of intratumoral macrophage by CD8+ T cells promotes severe intraocular inflammation that indirectly eliminates intraocular tumors by inducing phthisis. The immunosuppressive mechanisms which maintain ocular IP likely interfere with the interaction between CD8+ T cells and macrophage to limit immunosurveillance of intraocular tumors.
Publication Title
Splenectomy promotes indirect elimination of intraocular tumors by CD8+ T cells that is associated with IFNγ- and Fas/FasL-dependent activation of intratumoral macrophages.
Sample Metadata Fields
Specimen part, Treatment
View Samples- Mus musculus
- 6 Downloadable Samples
Description
On triggering of the T cell receptor CD8 T lymphocytes downregulate expression of the transcription factor KLF2. KLF2 expression remains low as these cells differentiate to Cytotoxic T lymphocytes (CTL) but may be re-expressed depending on the local environmental signals.
Publication Title
The impact of KLF2 modulation on the transcriptional program and function of CD8 T cells.
Sample Metadata Fields
Specimen part
View Samples- Mus musculus
- 11 Downloadable Samples
Description
In cytotoxic T cells (CTL), Protein Kinase B /Akt is activated by the T cell antigen receptor (TCR) and the cytokine Interleukin 2 (IL2), in part by phosophorylation of Akt by Phospholipid dependent kinase 1 (PDK1).
Publication Title
Protein kinase B controls transcriptional programs that direct cytotoxic T cell fate but is dispensable for T cell metabolism.
Sample Metadata Fields
Specimen part
View Samples- Mus musculus
- 6 Downloadable Samples
Description
Role for naturally occurring CD4+CD25+Foxp3+ regulatory T cells (nTregs) in counterbalancing this process. Using a transgenic murine model for autoimmune-mediated lung disease, we demonstrated that, despite pulmonary inflammation, lung-specific CD8+ T cells can reside quiescently in close proximity to self-antigen. Whereas self-reactive CD8+ T cells in the inflamed lung and lung-draining lymph nodes down-regulated the expression of effector molecules, those located in the spleen appeared to be partly antigen-experienced and displayed a memory-like phenotype. Since ex vivo-reisolated self-reactive CD8+ T cells were very well capable to respond to the antigen in vitro, we investigated a possible contribution of nTregs to the immune control over autoaggressive CD8+ T cells in the lung.
Publication Title
CD4+CD25+Foxp3+ regulatory T cells are dispensable for controlling CD8+ T cell-mediated lung inflammation.
Sample Metadata Fields
Specimen part
View Samples- Mus musculus
- 16 Downloadable Samples
Description
Hepatoblastoma (HB) is the most common pediatric liver tumor, and there are no targeted therapies available for children with HB. We have previously developed a murine model of HB which is driven by coactivation of the oncogenes YAP1 and -catenin (CTNNB1) [Tao J, Calvisi D, Ranganathan S, et al. Gastroenterology, 2014 Sep; 147(3): 690701]. We used the Sleeping Beauty transposase system combined with hydrodynamic tail vein injection to deliver plasmids containing mutant activated forms of YAP1 (YAP S127A) and -catenin (N90 -catenin) to a small number of pericentral hepatocytes. We have shown that these few transformed hepatocytes proliferate and dedifferentiate, eventually forming histologically heterogeneous tumors that resemble various subtypes of human HB (which is also highly heterogeneous), including areas of well-differentiated fetal, crowded fetal, embryonal, and blastemal HB. Our goal was to investigate how coactivation of YAP1 and -catenin drive the dedifferentiation of hepatocytes into hepatoblast-like tumor cells over time, leading to HB tumors. In order to measure changes in gene expression during tumorigenesis in our model, we used an Affymetrix microarray to analyze isolated RNA from wild type FVB mouse livers, mouse HB tumor tissue, and non-tumor liver tissue adjacent to HB tumors.
Publication Title
Hepatocyte-Derived Lipocalin 2 Is a Potential Serum Biomarker Reflecting Tumor Burden in Hepatoblastoma.
Sample Metadata Fields
Age, Specimen part
View Samples- Mus musculus
- 9 Downloadable Samples
Description
Epithelial-mesenchymal transition (EMT) has been linked to cancer progression and metastatic propensity. The 4T1 tumor is a clinically relevant model of spontaneous breast cancer metastasis. Here we characterize 4T1-derived cell lines for EMT, in vitro invasiveness and in vivo metastatic ability. Contrary to expectations, the 67NR cells, which form primary tumors but fail to metastasize, express vimentin and N-cadherin, but not E-cadherin. 4T1 cells, however, express E-cadherin, are highly migratory and invasive, and metastasize to multiple sites. The 66cl4 metastatic cells display mixed epithelial and mesenchymal markers, but are less migratory and invasive than 67NR cells. These findings demonstrate that the metastatic ability of breast cancer cells does not correlate with genotypic and phenotypic properties of EMT per se, and suggest that other processes may govern metastatic capability. Gene expression analysis also has not identified differences in EMT markers, but has identified several candidate genes that may influence metastatic ability.
Publication Title
Epithelial-mesenchymal transition (EMT) is not sufficient for spontaneous murine breast cancer metastasis.
Sample Metadata Fields
Sex, Specimen part
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GSE2843- Mus musculus
- 3 Downloadable Samples
Description
Glucocorticoids (GC) are in most chemotherapy protocols for lymphoid malignancies, particularly childhood acute lymphoblastic leukaemia (ALL) for their ability to induce apoptosis in malignant blast. The underlying mechanism, however, has so far only been investigated in model systems. This study comprises Affymetrix hgu133 plus 2.0 analyses of
Publication Title
Identification of glucocorticoid-response genes in children with acute lymphoblastic leukemia.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 34 Downloadable Samples
Description
Development of a suitable mouse model would facilitate the investigation of pathomechanisms underlying human psoriasis and would also assist in development of therapeutic treatments. However, while many psoriasis mouse models have been proposed, no single model recapitulates all features of the human disease, and standardized validation criteria for psoriasis mouse models have not been widely applied. In this study, whole-genome transcriptional profiling is used to compare gene expression patterns manifested by human psoriatic skin lesions with those that occur in five psoriasis mouse models (K5-Tie2, imiquimod, K14-AREG, K5-Stat3C and K5-TGFbeta1). While the cutaneous gene expression profiles associated with each mouse phenotype exhibited statistically significant similarity to the expression profile of psoriasis in humans, each model displayed distinctive sets of similarities and differences in comparison to human psoriasis. For all five models, correspondence to the human disease was strong with respect to genes involved in epidermal development and keratinization. Immune and inflammation-associated gene expression, in contrast, was more variable between models as compared to the human disease. These findings support the value of all five models as research tools, each with identifiable areas of convergence to and divergence from the human disease. Additionally, the approach used in this paper provides an objective and quantitative method for evaluation of proposed mouse models of psoriasis, which can be strategically applied in future studies to score strengths of mouse phenotypes relative to specific aspects of human psoriasis.
Publication Title
Genome-wide expression profiling of five mouse models identifies similarities and differences with human psoriasis.
Sample Metadata Fields
Specimen part
View Samples- Mus musculus
- 14 Downloadable Samples
Description
CD38, a multi-functional membrane receptor and enzyme, consumes NAD+ to generate products such as cyclic-ADP-ribose. CD38 knockout mice show elevated tissue and blood NAD+ level. Chronic feeding of high-fat, high-sucrose diet to wild type mice leads to exercise intolerance and reduced metabolic flexibility. Loss of CD38 by genetic mutation protects mice from diet-induced metabolic deficit. These animal model results suggest that elevation of tissue NAD+ through genetic ablation of CD38 can profoundly alter energy homeostasis in animals that are maintained on a calorically-excessive Western diet.
Publication Title
Genetic Ablation of CD38 Protects against Western Diet-Induced Exercise Intolerance and Metabolic Inflexibility.
Sample Metadata Fields
Specimen part
View Samples- Mus musculus
- 12 Downloadable Samples
Description
We assessed the impact of glucose transporter Glut2 gene inactivation in adult mouse liver (LG2KO mice). This suppressed hepatic glucose uptake but not glucose output. In the fasted state, expression of carbohydrate responsive element-binding protein (ChREBP) and its glycolytic and lipogenic target genes was abnormally elevated. Feeding, energy expenditure, and insulin sensitivity were identical in LG2KO and control mice. Glucose tolerance was normal early after Glut2 inactivation but intolerance developed at later time. This was caused by progressive impairment of glucose-stimulated insulin secretion even though beta-cell mass and insulin content remained normal. Liver transcript profiling revealed a coordinate down-regulation of cholesterol biosynthesis genes in LG2KO mice. This was associated with reduced hepatic cholesterol in fasted mice and a 30 percent reduction in bile acid production. We showed that chronic bile acids or FXR agonist treatment of primary islets increases glucose-stimulated insulin secretion, an effect not seen in islets from fxr-/- mice. Collectively, our data show that glucose sensing by the liver controls beta-cell glucose competence, through a mechanism that likely depends on bile acid production and action on beta-cells.
Publication Title
Hepatic glucose sensing is required to preserve β cell glucose competence.
Sample Metadata Fields
Specimen part
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