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SRP161856
Mus musculus
21 Downloadable Samples
NextSeq 500
Description
The adult heart contains macrophages derived from both embryonic and adult bone-marrow derived precursors. Such population diversity raises the possibility that macrophages of distinct origins occupy differing biological roles or anatomical niches within the heart. Here, we provide evidence for the latter, showing that bone-marrow derived macrophages express the chemokine receptor Ccr2 and preferentially localise to the aortic root of the heart. This targeted migration occurs via a Ccr2-Ccl7 axis, whereby Ccl7-producing cardiac fibroblasts populating the aortic root, recruit Ccr2pos macrophages. Notably, the selective recruitment of Ccr2pos macrophages renders the aortic root sensitive to inflammatory disease. In a mouse model of Kawasaki Disease, acute inflammation drives a numerical increase in bone-marrow derived Ccr2pos macrophages, which accumulate at the aorta and trigger local inflammation at this site. We propose that cardiac fibroblasts recruit Ccr2pos macrophages to the aortic root, and that this process targets inflammatory disease to the heart's major vessels. Overall design: Mice were either naïve or challenged with a Candida albicans water-soluble complex (CAWS) to induce a mouse model of Kawasaki Disease. Cardiac macrophages were extracted from three independent pools of naive mice and three independent pools of CAWS challenged mice. Splenic monocytes were extracted from three independent pools of naive mice. In each case, cardiac macrophages were divided into three subpopulations (R1, R2 and R3) based on Ccr2 and MHC-II expression.
Publication Title
The Selective Expansion and Targeted Accumulation of Bone Marrow-Derived Macrophages Drive Cardiac Vasculitis.
Sample Metadata Fields
Specimen part, Treatment, Subject
View Samples- Mus musculus
- 41 Downloadable Samples
Affymetrix Mouse Expression 430A Array (moe430a)
Description
Presbycusis age-related hearing loss is the number one communicative disorder of our aged population. Here we analyzed gene expression for a set of GABA receptors in the cochlea of aging CBA mice using the Affymetrix GeneChip MOE430A. Functional phenotypic hearing measures distortion-product otoacoustic emission (DPOAE) amplitudes (four age groups) were made. The gene expression changes from RMA normalized microarray data (40 replicates) were first subjected to one-way ANOVA, and then linear regression was performed. In addition, the log signal ratio was converted to fold change, and selected gene expression changes were confirmed by relative real-time PCR. Major findings: expression of GABA-A receptor subunit 6was upregulated with age and hearing loss, whereas subunit 1 was repressed. In addition, GABA-A receptor associated protein like-1 and GABA-A receptor associated protein like-2 were strongly downregulated with age and hearing impairment. Lastly, gene expression measures were correlated with pathway/network relationships relevant to the inner ear using Pathway Architect, to identify key pathways consistent with the gene expression changes observed.
Publication Title
Novel approach to select genes from RMA normalized microarray data using functional hearing tests in aging mice.
Sample Metadata Fields
Sex
View Samples- Mus musculus
- 9 Downloadable Samples
- Affymetrix Mouse Gene 1.0 ST Array (mogene10st)
Description
This study analyzes gene expression in beta-thalassemic fetal liver erythroblasts in the Th3 murine model. FACS-purified wild-type, heterozygous, and homozygous stage-matched erythroblasts from E14.5 fetal livers are compared.
Publication Title
Integrated protein quality-control pathways regulate free α-globin in murine β-thalassemia.
Sample Metadata Fields
Specimen part
View Samples- Mus musculus
- 32 Downloadable Samples
- Affymetrix Murine Genome U74A Version 2 Array (mgu74av2)
Description
Mouse inbred strains differ in many aspects of their phenotypes, and it is known that gene expression does so too. This gives us an opportunity to isolate the genetic aspect of variation in expression and compare it to other phenotypic variables. We have investigated these issues using an eight-strain expression profile comparison with four replicates per strain on Affymetrix MGU74av2 GeneChips focusing on one well-defined brain tissue (the hippocampus). We identified substantial strain-specific variation in hippocampal gene expression, with more than two hundred genes showing strain differences by a very conservative criterion. Many such genetically driven differences in gene expression are likely to result in functional differences including differences in behaviour. A large panel of inbred strains could be used to identify genes functionally involved in particular phenotypes, similar to genetic correlation. The genetic correlation between expression profiles and function is potentially very powerful, especially given the current large-scale generation of phenotypic data on multiple strains (the Mouse Phenome Project). As an example, the strongest genetic correlation between more than 200 probe sets showing significant differences among our eight inbred strains and a ranking of these strains by aggression phenotype was found for Comt, a gene known to be involved in aggression.
Publication Title
Hippocampal gene expression profiling across eight mouse inbred strains: towards understanding the molecular basis for behaviour.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 16 Downloadable Samples
- Illumina MouseRef-8 v2.0 expression beadchip
Description
Effective immune responses depend upon appropriate T cell differentiation in accord with the nature of an infectious agent, and the contingency of differentiation depends minimally on T cell antigen receptor, co-receptor, and cytokine signals. In this reverse genetic study we show that the Map Kinase, Erk2, is nonessential for T cell proliferation in the presence of optimum co-stimulation. Instead, it has opposite polar effects on T-bet and Gata3 expression and hence on Th1 and Th2 differentiation. Alternatively, in the presence of TGFbeta, the Erk pathway suppresses a large program of gene expression effectively limiting the differentiation of Foxp3+ T reg cells. In the latter case, the mechanisms involved include suppression of Gata3 and Foxp3, induction of Tbx21, phosphorylation of Smad2,3, and possibly suppression of Socs2, a positive inducer of Stat5 signaling. Consequently, loss of Erk2 severely impeded Th1 differentiation while enhancing the development of Foxp3+ induced T regulatory cells. Selected profiles of gene expression under multiple conditions of T cell activation illustrate the opposing consequences of Erk pathway signaling.
Publication Title
Polar opposites: Erk direction of CD4 T cell subsets.
Sample Metadata Fields
Specimen part, Time
View Samples- Mus musculus
- 8 Downloadable Samples
- Illumina HiSeq 2500
Description
Nonsyndromic clefts of the palate and/or lip are common birth defects arising in about 1/700 live births worldwide. They are caused by multiple genetic and environmental factors, can only be corrected surgically and require complex post-operative care that imposes significant burdens on individuals and society. Our understanding of the molecular networks that control palatogenesis has advanced through studies on mouse genetic models of cleft palate. In particular, the transcription factor Pax9 regulates palatogenesis through the Bmp, Fgf and Shh pathways in mice. But there is still much to learn about Pax9's relationship with other signaling pathways in this process. Expression analyses and unbiased gene expression profiling studies offer a molecular explanation for the resolution of palatal defects by showing that Wnt and Eda/Edar-related genes are expressed in normal palatal tissues and that the Wnt and Eda/Edar signaling pathway is downstream of Pax9 in palatogenesis. Overall design: E13.5 mouse embryos palate were micro-dissceted, control and mutant samples were seperated and individually lyzed for the RNA extraction.
Publication Title
Small-molecule Wnt agonists correct cleft palates in <i>Pax9</i> mutant mice <i>in utero</i>.
Sample Metadata Fields
Specimen part, Cell line, Treatment, Subject
View Samples- Mus musculus
- 1 Downloadable Sample
- Illumina HiSeq 2500
Description
Nonsyndromic clefts of the palate and/or lip are common birth defects arising in about 1/700 live births worldwide. They are caused by multiple genetic and environmental factors, can only be corrected surgically and require complex post-operative care that imposes significant burdens on individuals and society. Our understanding of the molecular networks that control palatogenesis has advanced through studies on mouse genetic models of cleft palate. In particular, the transcription factor Pax9 regulates palatogenesis through the Bmp, Fgf and Shh pathways in mice. But there is still much to learn about Pax9''s relationship with other signaling pathways in this process. Here we show alterations of Wnt expression and decreased Wnt activity in Pax9-/- palatal shelves are a likely result of Pax9''s ability to directly bind and repress the promoters of Dkk1 and Dkk2, proteins that antagonize Wnt signaling. We exploited this relationship by delivering small-molecule Dkk inhibitors into the tail-veins of pregnant Pax9+/- females from E10.5 to E14.5. Such therapies restored Wnt signaling, promoted cell proliferation, bone formation and fusion of palatal shelves in Pax9-/- embryos. These data uncover a connection between the roles of Pax9 and Wnt genes in palatogenesis and offer a new approach for treating human cleft palates. Overall design: E14 embryos of Pax9-/- and control littermates with or without WAY-262611 treatment, mouse embryos palate were micro-dissected, control and mutant samples were separated and individually lysed for the RNA extraction.
Publication Title
Small-molecule Wnt agonists correct cleft palates in <i>Pax9</i> mutant mice <i>in utero</i>.
Sample Metadata Fields
Specimen part, Cell line, Treatment, Subject
View Samples- Homo sapiens
- 23 Downloadable Samples
- IlluminaHiSeq2500
Description
Recently, we identified mesenchymoangioblast (MAB), as a clonal mesodermal precursor for mesenchymal and endothelial cells. Here we show, that MABs have the capacity to produce mesenchymal progenitors, which can be differentiated into pericytes or smooth muscles cells under the influence of PDGF-BB or TGFß plus sphingosylphosphorylcholine (SPC), respectively. Based on these studies we established the hierarchy of vasculogenic progenitors that provides the platform for interrogation of molecular mechanisms regulating vasculogenic cell specification and diversification from primitive posterior mesoderm. Overall design: Vasculogenic cells generated under specific culture conditions. Primary cells were used as control.
Publication Title
Specification and Diversification of Pericytes and Smooth Muscle Cells from Mesenchymoangioblasts.
Sample Metadata Fields
No sample metadata fields
View Samples- Homo sapiens
- 48 Downloadable Samples
- Illumina HiSeq 2500
Description
We decribe the accessible chormatin landscape in RAS-induced (RIS) and NOTCH induced senescence (NIS) using ATAC-seq. By expressing active NOTCH (N1ICD) in the context of RIS, we find that N1ICD antagonises the formation of accessible regions in RIS. By performing co-cultures, we demonstrate that cells expressing a NOTCH1 ligand, JAGGED1, can antagonise the formation of RIS specific accessible regions. Overall design: mRNA profiles were IMR90 cells expressing ER:HRAS(G12V) and a control vector or MSCV miR30 shHMGA1 were generated. 6 biological replicates.
Publication Title
NOTCH-mediated non-cell autonomous regulation of chromatin structure during senescence.
Sample Metadata Fields
Cell line, Subject
View Samples- Homo sapiens
- 23 Downloadable Samples
- Illumina HumanHT-12 V4.0 expression beadchip
Description
Methods for identifying protein-protein interactions have mostly been limited to tagged exogenous expression approaches. We now establish a rapid, robust and comprehensive method for finding interacting proteins using endogenous proteins from limited cell numbers. We apply this approach called Rapid IP-Mass Spectrometry of Endogenous proteins (RIME) to identify ER, FoxA1 and E2F4 interacting proteins in breast cancer cells. From small numbers of starting cells, we find a comprehensive collection of known ER, FoxA1 and E2F4 targets, plus a number of novel unexpected interactors. One of the most ER (and FoxA1) associated interactors is GREB1, an estrogen induced gene with almost no known function. We apply RIME, in parallel with ER ChIP-seq, to identify ER protein interactors and ER binding events from solid tumor xenografts, resulting in the validation of the ER-GREB1 interactions. Furthermore, we establish a method for identifying endogenous interacting proteins from solid primary breast cancer samples, whih we apply to validate ER interactions with GREB1 and additional co-factors. Mechanistically, we show that GREB1 is recruited with ER to the chromatin where it functions as an essential estrogen-mediated regulatory factor required for effective ER transcriptional activity. Our novel approach enables, for the first time, the ability for discovery and validation of protein-protein interactions in whole tissue and solid tumors, revealing significant insight into ER regulatory factors.
Publication Title
Endogenous purification reveals GREB1 as a key estrogen receptor regulatory factor.
Sample Metadata Fields
Cell line, Treatment
View Samples