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GSE10273
Mus musculus
9 Downloadable Samples
Description
Productive rearrangement of the immunoglobulin heavy chain locus triggers a major developmental checkpoint that promotes limited clonal expansion of pre-B cells, culminating in cell cycle arrest and rearrangement of the kappa () or lambda () light-chain loci. B lineage cells lacking the related transcription factors IRF-4 and IRF-8 undergo a developmental arrest at the cycling pre-B cell stage and are blocked for light-chain recombination. Using Irf-4,8-/- pre-B cells we demonstrate that two pathways converge to synergistically drive light-chain rearrangement, a process that is not simply activated by cell cycle exit. One pathway is directly dependent on IRF-4, whose expression is elevated by pre-BCR signaling. IRF-4 targets the 3 and enhancers to increase locus accessibility and positions a kappa allele away from pericentromeric heterochromatin. The other pathway is triggered by attenuation of IL-7 signaling and results in activation of the intronic enhancer via binding of the transcription factor, E2A. Intriguingly, IRF-4 regulates the expression of CXCR4 and promotes the migration of pre-B cells in response to the chemokine CXCL12. We propose that IRF-4 coordinates the two pathways regulating light-chain recombination by positioning pre-B cells away from IL-7 expressing stromal cells.
Publication Title
Regulation of immunoglobulin light-chain recombination by the transcription factor IRF-4 and the attenuation of interleukin-7 signaling.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 6 Downloadable Samples
Description
Nuclear compartmentalization appears to play an important role in regulating metazoan genes. While studies on immunoglobulin (Ig) and other loci have correlated positioning at the nuclear lamina with gene repression, the functional consequences of this compartmentalization remain untested. We devised an approach for inducible tethering of genes to the inner nuclear membrane (INM) and demonstrate with 3D DNA-ImmunoFISH, repositioning of chromosomal regions to the nuclear lamina. Relocalization requires mitotic nuclear envelope breakdown and reformation. Tethering leads to the accumulation of lamin and INM proteins but not to association with pericentromeric heterochromatin or nuclear pore complexes. Recruitment of genes to the INM can result in their transcriptional repression. Using DamID we show that as is the case for our model system, inactive Ig loci at the nuclear periphery are contacted by INM and lamina components. We propose that such molecular interactions are used to compartmentalize and limit the accessibility of Ig loci.
Publication Title
No associated publication
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 24 Downloadable Samples
Description
Particulate Matter Triggers Carotid Body Dysfunction, Respiratory Dysynchrony and Cardiac Arrhythmias in Mice with Cardiac Failure
Publication Title
Particulate matter induces cardiac arrhythmias via dysregulation of carotid body sensitivity and cardiac sodium channels.
Sample Metadata Fields
Age, Specimen part
View Samples- Mus musculus
- 12 Downloadable Samples
Description
We have previously demonstrated that pre-B-cell colony enhancing factor (PBEF) ais a biomarker in sepsis and sepsis-induced acute lung injury (ALI) with genetic variants conferring ALI susceptibility118. In the current study, we explored the mechanistic participation of PBEF in ALI and ventilator-induced associated lung injury (VIALI). Initial in vitro studies and demonstrated rhPBEF aas a direct rat neutrophil chemotactic factor in vitro producing marked in vivo increases in BAL leukocytes (PMNs) in vivo following (intratracheal injection (,IT) in C57B6 mice. These latter changes were accompanied by increased BAL levels of the PMN chemoattractants (, KC and MIP2), and modest changes in lung vascular and but were not associated with significant increasesin alveolar permeability. We next explored the potential synergism between rhPBEF administration (IT) and a mechanical ventilation model of modest VILI lung injury (4 hours, 30 ml/kg tidal volume). We and observed dramatic synergistic increases in BAL PMNs, and both BAL protein and cytokine levels (IL-6, TNF-?, KC). Gene expression profiling Microarray analysis further supported a major role for PBEF in the induction of gene modules associated with ALI and VALI (NFkB pathway, leukocyte extravasation, apoptosis, toll receptor signaling). Finally, we exposed wild type and heterozygous PBEF+/- mice (targeted deletion of a single PBEF allele deletion) to a model of severe VILImechanical ventilation-induced lung injury (4 hours, 40 ml/kg tidal volume). PBEF+/- mice were significantly protected from VIALI-associated increases in BAL protein and BAL IL-6 levels and exhibited significantly reduced expression of ALI-associated gene expression modules. Together, these results indicate that PBEF is a key inflammatory mediator intimately involved in both the development and severity of ventilator-induced ALI.
Publication Title
Essential role of pre-B-cell colony enhancing factor in ventilator-induced lung injury.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 11 Downloadable Samples
Description
Background: Microvascular injury and increased vascular leakage are prominent features of the radiation-induced lung injury (RILI) which follows cancerassociated thoracic irradiation. The mechanisms of RILI are incompletely understood and therapeutic strategies to limit RILI are currently unavailable. We established a murine model of radiation pneumonitis in order to assess mechanism-based therapies for RILI-induced inflammation and vascular barrier dysfunction. Based on prior studies, we investigated the therapeutic potential of simvastatin as a vascular barrier protective agent in RILI.
Publication Title
Simvastatin attenuates radiation-induced murine lung injury and dysregulated lung gene expression.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 8 Downloadable Samples
Description
Diet-induced obesity (DIO) is rapidly becoming a global health problem, particularly as Westernization of emerging nations continues. Currently, one third of adult Americans are considered obese and, if current trends continue, >90% of US citizens are predicted to be affected by 2050. However, efforts to fight this epidemic have not yet produced sound solutions for prevention or treatment. Our studies reveal a balanced and chronobiological relationship between food consumption, daily variation in gut microbial evenness and function, basomedial hypothalamic circadian clock (CC) gene expression, and key hepatic metabolic regulatory networks , including CC and nuclear receptors (NR), that is are essential for metabolic homeostasis. Western diets high in saturated fats dramatically alter diurnal variation in microbial composition and function, which in turn lead to uncoupling of the hepatic CC and NR networks from central CC control in ways that offset the timing and types of regulatory factors directing metabolic function. These signals include microbial metabolites such as short chain fatty acids (SCFAs) and hydrogen sulfide (H2S) that can directly regulate or disrupt metabolic networks of the hepatocyte. Our study therefore provides insights into the complex and dynamic relationships between diet, gut microbes, and the host that are critical for maintenance of health. Perturbations of this constellation of processes, in this case by diet-induced dysbiosis and its metabolomic signaling, can potentially promote metabolic imbalances and disease. This knowledge opens up many possibilities for novel therapeutic and interventional strategies to treat and prevent DIO, ranging from the manipulation of gut microbial function to pharmacological targeting of host pathways to restore metabolic balance.
Publication Title
Effects of diurnal variation of gut microbes and high-fat feeding on host circadian clock function and metabolism.
Sample Metadata Fields
Specimen part
View Samples- Mus musculus
- 6 Downloadable Samples
Description
Gata5 is a zinc finger transcription factor that is expressed in embryonic pulmonary mesenchyme and becomes upregulated in the lungs, gut, and bladder during postnatal development. We used microarray to comapre gene expression profiles of mouse lung between Gata5 knockout and wild type mice. We hope to identify the differentially expressed genes that affected by Gata5 gene deletion and their functional clusters or pathways.
Publication Title
No associated publication
Sample Metadata Fields
Specimen part
View Samples- Mus musculus
- 6 Downloadable Samples
Description
effect of over-expression LIGHT on T cells for the liver gene expression
Publication Title
Lymphotoxin beta receptor-dependent control of lipid homeostasis.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 1 Downloadable Sample
Description
Diabetogenic CD8+ G9C8 clone cells and the T cells from a transgenic mouse bearing the same TCR as the clone, displayed differences in their ability to induce disease in vivo.Microarray analysis was done to identify the molecular basis for such differences between the two sets of CD8 T cells.
Publication Title
Cytotoxic mechanisms employed by mouse T cells to destroy pancreatic β-cells.
Sample Metadata Fields
Specimen part, Disease
View Samples- Mus musculus
- 16 Downloadable Samples
Description
Clinical studies have revealed that social support improves the outcome of cancer patients while epidemiological studies suggest that social isolation increases the risk of death associated with several chronic diseases. However, the precise biological consequences of an unfavorable social environment have not been defined. To do so, robust, reproducible pre-clinical models are needed to study the mechanisms whereby an adverse environment impacts on gene expression and cancer biology. Because random assignment of inbred laboratory mice to well-defined social environments allows accurate and repeated measurements of behavioral and endocrine parameters, transgenic mice provide a pre-clinical framework with which to begin to determine gene-environment mechanisms. In this study, we found that female C3(1)/SV40 T-antigen mice deprived of social interaction from weaning exhibited increased expression of genes encoding key metabolic pathway enzymes in the pre-malignant mammary gland. Chronic social isolation was associated with upregulated fatty acid synthesis and glycolytic pathway gene expression - both pathways known to contribute to increased breast cancer growth. Consistent with the expression of metabolic genes, isolated mice subsequently developed significantly larger mammary gland tumors compared to group-housed mice. Endocrine evaluation confirmed that isolated mice developed a heightened corticosterone stress response compared to group-housed mice. Together, these transdisciplinary studies show for the first time that an adverse social environment is associated with altered mammary gland gene expression and tumor growth. Moreover, the identification of specific alterations in metabolic pathways favoring tumor growth suggests potential molecular biomarkers and/or targets (e.g. fatty acid synthesis) for preventive intervention in breast cancer.
Publication Title
No associated publication
Sample Metadata Fields
Sex, Age, Specimen part
View Samples