Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA274617 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR1790440.fastq.gz | Fastqsanger.gz | |||
| SRR1790441.fastq.gz | Fastqsanger.gz | |||
| SRR1790442.fastq.gz | Fastqsanger.gz | |||
| SRR1790443.fastq.gz | Fastqsanger.gz | |||
| SRR1790444.fastq.gz | Fastqsanger.gz |
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Project description:3’,5’-cyclic adenosine monophosphate (cAMP) is an ubiquitous second messenger which regulates multiple physiological functions by acting in distinct subcellular microdomains. Although several targeted cAMP biosensors have been developed and used in cell lines or neonatal cardiomyocytes, it is unclear whether such biosensors can be successfully used in vivo, especially in the context of disease. Here, we generated the first transgenic mouse model expressing a targeted cAMP sensor (Epac1-PLN) and analyzed microdomain-specific second messenger dynamics in the vicinity of the sarcoplasmic reticulum calcium ATPase (SERCA). We demonstrate the biocompatibility of this targeted sensor and its potential for real-time monitoring of compartmentalized cAMP signaling in adult cardiomyocytes isolated from healthy mouse heart and from in vivo cardiac disease model. Finally, we used gene arrays to verify that the mRNA expression levels of the main players involved in cAMP signaling such as beta-ARs, G-protein, adenylyl cyclases, PKAs, PDEs, and Epac were not significantly changed between wildtype and transgenic Epac1-PLN expressing cardiomyocytes. To compare cardiac specific mRNA expression between wildtype and Epac1-PLN transgenic mice, cardiomyocyte RNA from total of 5 individual wildtype and 5 Epac1-PLN transgenic mice was isolated and submitted for the Illumina gene array analysis to the Göttingen transcriptome analysis laboratory (TAL).
2015-03-02 | E-GEOD-65651 | biostudies-arrayexpress
Project description:These mice have been genetically modified so that the mouse PLN gene has been replace with the human PLN gene. Phopspholamban (PLN), the reversible inhibitor of the sarcoplasmic reticulum (SR) Ca2+-ATPase (SERCA2a), is a key regulator of myocyte Ca2+-cycling with a significant role in heart failure. We previously showed that the single amino acid difference between human and mouse PLN results in increased inhibition of Ca2+-cycling, cardiac remodeling and attenuated stress responses, in transgenic mice expressing the human PLN in the null background (hPLN). This set of microarray experiments aimed at deciphering the molecular mechanisms implicated in this process. 6 wild type, 6 transgenic mice. All at 11 weeks of age. FVB/N background. Whole hearts isolated, snap frozen and used for total RNA extraction.
2011-12-15 | E-GEOD-20172 | biostudies-arrayexpress
Project description:These mice have been genetically modified so that the mouse PLN gene has been replace with the human PLN gene. Phopspholamban (PLN), the reversible inhibitor of the sarcoplasmic reticulum (SR) Ca2+-ATPase (SERCA2a), is a key regulator of myocyte Ca2+-cycling with a significant role in heart failure. We previously showed that the single amino acid difference between human and mouse PLN results in increased inhibition of Ca2+-cycling, cardiac remodeling and attenuated stress responses, in transgenic mice expressing the human PLN in the null background (hPLN). This set of microarray experiments aimed at deciphering the molecular mechanisms implicated in this process.
2011-12-15 | GSE20172 | GEO
Project description:Aims: A mutation in the phospholamban (PLN) gene, leading to deletion of Arg14 (R14del), has been associated with malignant arrhythmias and ventricular dilation. Identifying pre-symptomatic carriers with vulnerable myocardium is crucial because arrhythmia can result in sudden cardiac death, especially in young adults with PLN-R14del mutation. This study aimed at assessing the efficiency and efficacy of in vivo genome editing, using CRISPR/Cas9 and a cardiotropic adeno-associated virus (AAV9), in improving cardiac function in young adult mice expressing the human PLN-R14del. Methods and Results: Humanized mice were generated expressing human wild-type (hPLN-WT) or mutant (hPLN-R14del) PLN in the heterozygous state, mimicking human carriers. Cardiac magnetic resonance imaging at 12 weeks of age showed bi-ventricular dilation and increased stroke volume in mutant vs. WT mice, with no deficit in ejection fraction or cardiac output. Challenge of ex vivo hearts with isoproterenol and rapid pacing unmasked higher propensity for sustained ventricular tachycardia (VT) in hPLN-R14del relative to hPLN-WT. Specifically, the VT threshold was significantly reduced (20.3±1.2 Hz in hPLN-R14del vs. 25.7±1.3 Hz in WT, p<0.01) reflecting higher arrhythmia burden. To inactivate the R14del allele, mice were tail-vein-injected with AAV9.CRISPR/Cas9/gRNA or AAV9 empty capsid (controls). CRISPR-Cas9 efficiency was evaluated by droplet digital PCR and NGS-based amplicon sequencing. In vivo gene editing significantly reduced end diastolic and stroke volumes in hPLN-R14del CRISPR-treated mice compared to controls. Susceptibility to VT was also reduced, as the VT threshold was significantly increased relative to controls (30.9±2.3 Hz vs. 21.3±1.5 Hz; p<0.01). Conclusions: This study is the first to show that disruption of hPLN-R14del allele by AAV9- CRISPR/Cas9 improves cardiac function and reduces VT susceptibility in humanized PLN-R14del mice, offering preclinical evidence for translatable approaches to therapeutically suppress the arrhythmogenic phenotype in human patients with PLN-R14del disease.
2023-03-11 | PXD031612 | Pride
Project description:3’,5’-cyclic adenosine monophosphate (cAMP) is an ubiquitous second messenger which regulates multiple physiological functions by acting in distinct subcellular microdomains. Although several targeted cAMP biosensors have been developed and used in cell lines or neonatal cardiomyocytes, it is unclear whether such biosensors can be successfully used in vivo, especially in the context of disease. Here, we generated the first transgenic mouse model expressing a targeted cAMP sensor (Epac1-PLN) and analyzed microdomain-specific second messenger dynamics in the vicinity of the sarcoplasmic reticulum calcium ATPase (SERCA). We demonstrate the biocompatibility of this targeted sensor and its potential for real-time monitoring of compartmentalized cAMP signaling in adult cardiomyocytes isolated from healthy mouse heart and from in vivo cardiac disease model. Finally, we used gene arrays to verify that the mRNA expression levels of the main players involved in cAMP signaling such as beta-ARs, G-protein, adenylyl cyclases, PKAs, PDEs, and Epac were not significantly changed between wildtype and transgenic Epac1-PLN expressing cardiomyocytes.
2015-03-02 | GSE65651 | GEO
Project description:Analysis of the transcriptome of cardiac tissue from mice transgenically expressing human cardiolipin synthesis. The hypothesis tested was that cardiac specific transgenic expression of cardiolipin synthase alters myocardial lipidomic flux resulting in compensatory metabolic gene transcriptional changes that will attenuate pathological environmental and dietary insults on bioenergetics. Total RNA obtained from cardiac tissue from transgenic cardiac specific expressing human cardiolipin synthase 1 (hCLS1) mouse model at 4 months of age compared to wildtype littermates
2011-11-05 | E-GEOD-33451 | biostudies-arrayexpress
Project description:ER71 mutant embryos are nonviable and lack hematopoietic and endothelial lineages. To further define the functional role for ER71 in cell lineage decisions, we generated genetically modified mouse models. We engineered an ER71-EYFP transgenic mouse model by fusing the 3.9 kb ER71 promoter to the EYFP reporter gene. Using FACS and transcriptional profiling, we examined the EYFP+ populations of cells in ER71 mutant and wildtype littermates. In the absence of ER71, we observed an increase in the number of EYFP expressing cells, increased expression of the cardiac molecular program and decreased expression of the hemato-endothelial program compared to the wildtype littermate controls. We have also generated a novel ER71-Cre transgenic mouse model using the same 3.9 kb ER71 promoter. Genetic fate mapping studies revealed that the ER71 expressing cells daughter hematopoietic and endothelial lineages in the wildtype background. In the absence of ER71, these cell populations contributed to alternative mesodermal lineages including the cardiac lineage. To extend these analyses, we used an inducible ES/EB system and observed that ER71 overexpression repressed cardiogenesis. Together, these studies identify ER71 as a critical regulator of mesodermal fate decisions, acting to specify the hematopoietic and endothelial lineages at the expense of cardiac lineages. This enhances our understanding of the mechanisms that govern mesodermal fate decisions early during embryogenesis. 12samples were analyzed, including triplicates of WT; EYFP positive, WT EYFP negative, ER71 MT; EYFP positive and ER71 MT; EYFP negative cells
2011-11-02 | E-GEOD-32223 | biostudies-arrayexpress
Project description:Project Description(50 to 5000 characters):Phospholamban (PLN) plays a central role in Ca2+ homeostasis in cardiac myocytes through its regulation of the SERCA2A Ca2+ pump. An inherited mutation converting arginine residue 9 in PLN to cysteine (R9C) results in dilated cardiomyopathy (DCM) in both humans and transgenic mice, but the downstream signaling defects leading to heart failure are poorly understood. Here, we used precision tandem mass spectrometry to gain unbiased insights into the global phosphorylation dynamics of 2041 cardiac phosphoproteins in early affected heart tissue in the transgenic R9C mouse model of DCM compared to wild type littermates. 251 dysregulated phosphorylation sites were quantified after affinity capture and identification of 4337 phosphopeptides from fractionated whole heart homogenates. Enrichment analysis of the differential phosphoprotein patterns revealed dozens of signaling pathways regulating cardiovascular activity that are selectively impaired in early stages of DCM. Strikingly, dysregulated signaling through the Notch-1 receptor, recently linked to cardiomyogenesis and embryonic cardiac stem cell development and differentiation but never directly implicated in DCM before, was one of the most prominently perturbed pathways. We verified dysregulation of Notch1 downstream components in early symptomatic R9C transgenic mouse hearts compared to wild type by immunoblot analysis and confocal immunofluorescence microscopy. These data reveal unexpected connections between protein kinases, cell signaling networks and downstream effectors essential for proper cardiac function
2016-12-12 | PXD004810 | Pride
Project description:Metabolic labeling of glycans with clickable unnatural sugars has enabled glycan imaging and glycoproteomics in mixed cell populations. However, in vivo labeling and profiling of cell-type-specific glycans remains challenging. Here, we develop genetically encoded metabolic glycan labeling (GeMGL), a cell-type-specific strategy based on a bump-hole pair of an unnatural sugar and its matching engineered enzyme. N pentynylacetylglucosamine (GlcNAl) serves as a bumped analog of N acetylglucosamine (GlcNAc) that can be specifically incorporated into glycans of cells expressing an engineered mutant of UDP-GlcNAc pyrophosphorylase, AGX2F383G. GeMGL with the 1,3-di-O-propionylated GlcNAl (1,3-Pr2GlcNAl) and AGX2F383G pair is demonstrated in cell co-cultures, and used for specific labeling of glycans in mouse xenograft tumors. By generating a transgenic mouse line with AGX2F383G expressed under cardiomyocyte-specific promoter, we perform specific imaging of cardiomyocyte glycans in the heart and identified 582 cardiomyocyte O-GlcNAcylated proteins with no interference from other cardiac cell types. GeMGL will facilitate cell-type-specific glycoproteomics in various tissues and disease models.
2022-02-28 | PXD030663 | Pride
Project description:ER71 mutant embryos are nonviable and lack hematopoietic and endothelial lineages. To further define the functional role for ER71 in cell lineage decisions, we generated genetically modified mouse models. We engineered an ER71-EYFP transgenic mouse model by fusing the 3.9 kb ER71 promoter to the EYFP reporter gene. Using FACS and transcriptional profiling, we examined the EYFP+ populations of cells in ER71 mutant and wildtype littermates. In the absence of ER71, we observed an increase in the number of EYFP expressing cells, increased expression of the cardiac molecular program and decreased expression of the hemato-endothelial program compared to the wildtype littermate controls. We have also generated a novel ER71-Cre transgenic mouse model using the same 3.9 kb ER71 promoter. Genetic fate mapping studies revealed that the ER71 expressing cells daughter hematopoietic and endothelial lineages in the wildtype background. In the absence of ER71, these cell populations contributed to alternative mesodermal lineages including the cardiac lineage. To extend these analyses, we used an inducible ES/EB system and observed that ER71 overexpression repressed cardiogenesis. Together, these studies identify ER71 as a critical regulator of mesodermal fate decisions, acting to specify the hematopoietic and endothelial lineages at the expense of cardiac lineages. This enhances our understanding of the mechanisms that govern mesodermal fate decisions early during embryogenesis.
2011-11-02 | GSE32223 | GEO