Mus musculus
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ABSTRACT:
PROVIDER: PRJNA93583 | ENA |
REPOSITORIES: ENA
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Project description:Three major MAP kinase signaling cascades, ERK, p38 and JNK, play significant roles in the development of cardiac hypertrophy and heart failure in response to external stress and neural/hormonal stimuli. In order to study the specific function of each MAP kinase branch in adult heart, we have generated three transgenic mouse models with cardiac specific and temporally regulated expression of activated mutants of Ras, MKK3 and MKK7, which are selective upstream activators for ERK, p38 and JNK, respectively. Gene expression profiles in transgenic adult hearts were determined using cDNA microarrays at both early (4-7 days) and late (2-4 weeks) time points following transgene induction. From this study, we revealed common changes in gene expression among the three models, particularly involving extracellular matrix remodeling. However, distinct expression patterns characteristic for each pathway were also identified in cell signaling, growth and physiology. In addition, genes with dynamic expression differences between early vs. late stages illustrated primary vs. secondary changes upon MAP kinase activation in adult hearts. These results provide an overview to both short term and long term effects of MAP kinase activation in heart and support some common as well as unique roles for each MAP kinase cascade in the development of heart failure. Keywords: MAP Kinase induction comparison, time course
2005-11-01 | GSE3530 | GEO
Project description:Three major MAP kinase signaling cascades, ERK, p38 and JNK, play significant roles in the development of cardiac hypertrophy and heart failure in response to external stress and neural/hormonal stimuli. In order to study the specific function of each MAP kinase branch in adult heart, we have generated three transgenic mouse models with cardiac specific and temporally regulated expression of activated mutants of Ras, MKK3 and MKK7, which are selective upstream activators for ERK, p38 and JNK, respectively. Gene expression profiles in transgenic adult hearts were determined using cDNA microarrays at both early (4-7 days) and late (2-4 weeks) time points following transgene induction. From this study, we revealed common changes in gene expression among the three models, particularly involving extracellular matrix remodeling. However, distinct expression patterns characteristic for each pathway were also identified in cell signaling, growth and physiology. In addition, genes with dynamic expression differences between early vs. late stages illustrated primary vs. secondary changes upon MAP kinase activation in adult hearts. These results provide an overview to both short term and long term effects of MAP kinase activation in heart and support some common as well as unique roles for each MAP kinase cascade in the development of heart failure. Experiment Overall Design:MHC-floxed-HRas-v12/MKK3bE/MKK7D transgenic mice were bred with MHC-Mer-Cre-Mer (MCM) mice (from Dr. J. Molkentin, Cincinnati Children's Hospital) to generate double transgenic animals harboring both floxed transgenes and Mer-Cre-Mer transgene. At 12 weeks of age the double transgenic mice and non-transgenic littermate controls were treated via i.p. injection of tamoxifen at a dosage of 20mg/kgBW once a day for 3 consecutive days as reported. The hearts were harvested at an early (4-7 days post first tamoxifen injection) and a late (2-4 weeks) time point. Left ventricles were dissected and rapidly frozen in liquid nitrogen and stored at -80C prior to protein and RNA analysis. Transcription profiling of
2007-10-12 | E-GEOD-3530 | biostudies-arrayexpress
Project description:The adult mammalian heart is incapable of regeneration following injury. In contrast, the neonatal mouse heart can efficiently regenerate during the first week of life. The molecular mechanisms that mediate the regenerative response and its blockade in later life are not understood. Here, by single-nucleus RNA sequencing, we map the dynamic transcriptional landscape of five distinct cardiomyocyte populations in healthy, injured and regenerating mouse hearts. We identify immature cardiomyocytes that enter the cell-cycle following injury and disappear as the heart loses the ability to regenerate. These proliferative neonatal cardiomyocytes display a unique transcriptional program dependent on NFYa and NFE2L1 transcription factors, which exert proliferative and protective functions, respectively. Cardiac overexpression of these two factors conferred protection against ischemic injury in mature mouse hearts that were otherwise non-regenerative. These findings advance our understanding of the cellular basis of neonatal heart regeneration and reveal a transcriptional landscape for heart repair following injury.
2020-03-18 | GSE130699 | GEO
Project description:The adult mammalian heart is incapable of regeneration following injury. In contrast, the neonatal mouse heart has a transient ability to regenerate, however the molecular mechanism that mediates this regenerative response is not fully understood. Here, by single-nucleus RNA sequencing we map the transcriptome landscape of cardiomyocytes in neonatal mouse hearts at healthy, regenerative, and remodeling conditions. We show that an immature cardiomyocyte population enters cell-cycle in response to injury. Absence of this cardiomyocyte population overtime is associated with the loss of the ability of the heart to regenerate. We show a defined injury response in these cardiomyocytes, including activation of transcription factors NFYa and NFE2L1, which play proliferative and protective roles, respectively. We further show that overexpression of these two factors in vivo promotes heart regeneration. Thus, these findings refined our understanding of cellular basis of neonatal heart regeneration and reveal dynamic transcriptome landscape of cardiomyocytes in response to injury.
2020-03-18 | GSE142364 | GEO
Project description:The adult mammalian heart is incapable of regeneration following injury. In contrast, the neonatal mouse heart has a transient ability to regenerate, however the molecular mechanism that mediates this regenerative response is not fully understood. Here, by single-nucleus RNA sequencing we map the transcriptome landscape of cardiomyocytes in neonatal mouse hearts at healthy, regenerative, and remodeling conditions. We show that an immature cardiomyocyte population enters cell-cycle in response to injury. Absence of this cardiomyocyte population overtime is associated with the loss of the ability of the heart to regenerate. We show a defined injury response in these cardiomyocytes, including activation of transcription factors NFYa and NFE2L1, which play proliferative and protective roles, respectively. We further show that overexpression of these two factors in vivo promotes heart regeneration. Thus, these findings refined our understanding of cellular basis of neonatal heart regeneration and reveal dynamic transcriptome landscape of cardiomyocytes in response to injury.
2020-03-18 | GSE142365 | GEO
Project description:The Ciona heart progenitor lineage (TVC, trunk ventral cells) is first specified by Fibroblast Growth Factor/Map Kinase (FGF/MapK) activation of the transcription factor Ets1/2 (Ets). For this analysis, B7.5 lineage cells were labeled with the Mesp-GFP reporter. In the first experiment, we targeted a dominant-negative form of the sole Ciona FGF receptor (FGFRdn) to the B7.5 lineage using the Mesp enhancer (Mesp-FGFRdn). In the second experiment, we targeted a dominant repressor form of Ets1/2 to the B7.5 lineage using the Mesp enhancer (Mesp-EtsWRPW). This construct is designed to repress Ets1/2 target gene transcription and has previously been shown to abolish TVC induction. We employed whole-genome microarray analysis of sorted B7.5 lineage cells to identify primary FGF:MapK:Ets1/2 target genes.
2012-06-04 | E-GEOD-38313 | biostudies-arrayexpress
Project description:The implementations of targeted molecular therapies and immunotherapy in melanoma vastly improved the therapeutic outcome in patients with limited efficacy of surgical intervention. Nevertheless, a large fraction of melanoma patients still remains refractory or acquires resistance to these new forms of treatment, illustrating a need for improvement. Here we report that the clinically relevant combination of MAP kinase inhibitors Dabrafenib and Trametinib synergizes with RIG-I agonist-induced immunotherapy to kill BRAF-mutated human and mouse melanoma cells. Kinase inhibition did not compromise the agonist-induced innate immune response of the RIG-I pathway in host immune cells. In a melanoma transplantation mouse model, the triple therapy outperformed the individual therapies. Our study suggests that targeted activation of RIG-I with its synthetic ligand 3pRNA could vastly improve tumor control in a substantial fraction of melanoma patients receiving MAP kinase inhibitors.
2024-07-26 | GSE268982 | GEO
Project description:The implementations of targeted molecular therapies and immunotherapy in melanoma vastly improved the therapeutic outcome in patients with limited efficacy of surgical intervention. Nevertheless, a large fraction of melanoma patients still remains refractory or acquires resistance to these new forms of treatment, illustrating a need for improvement. Here we report that the clinically relevant combination of MAP kinase inhibitors Dabrafenib and Trametinib synergizes with RIG-I agonist-induced immunotherapy to kill BRAF-mutated human and mouse melanoma cells. Kinase inhibition did not compromise the agonist-induced innate immune response of the RIG-I pathway in host immune cells. In a melanoma transplantation mouse model, the triple therapy outperformed the individual therapies. Our study suggests that targeted activation of RIG-I with its synthetic ligand 3pRNA could vastly improve tumor control in a substantial fraction of melanoma patients receiving MAP kinase inhibitors.
2024-06-04 | GSE269008 | GEO
Project description:Sustained Akt activation induces cardiac hypertrophy (LVH), which may lead to heart failure. This study tested the hypothesis that Akt activation contributes to mitochondrial dysfunction in pathological LVH. Akt activation induced LVH and progressive repression of mitochondrial fatty acid oxidation (FAO) pathways. Preventing LVH by inhibiting mTOR failed to prevent the decline in mitochondrial function but glucose utilization was maintained. Akt activation represses expression of mitochondrial regulatory, FAO, and oxidative phosphorylation genes in vivo that correlate with the duration of Akt activation in part by reducing FOXO-mediated transcriptional activation of mitochondrial-targeted nuclear genes in concert with reduced signaling via PPARα/PGC-1α and other transcriptional regulators. In cultured myocytes Akt activation disrupted mitochondrial bioenergetics, which could be partially reversed by maintaining nuclear FOXO, but not by increasing PGC-1α. Thus, although short-term Akt activation may be cardioprotective during ischemia by reducing mitochondrial metabolism and increasing glycolysis, long-term Akt activation in the adult heart contributes to pathological LVH in part by reducing mitochondrial oxidative capacity. Three samples per group of 8-week-old wild-type or transgenic mice with cardiac-specific constitutive expression of an activated Akt (caAkt) in the heart at 8 weeks of age were used. Mice have been previously described in depth (Shioi T, McMullen JR, Kang PM, Douglas PS, Obata T, Franke TF, Cantley LC, Izumo S. 2002. Akt/protein kinase B promotes organ growth in transgenic mice. Mol. Cell. Biol. 22:2799-2809.). After hearts were removed total myocardial RNA was labeled and processed as described below for microarray analysis to detail the global changes in gene expression underlying development of heart failure in this mouse model.
2015-01-05 | E-GEOD-63848 | biostudies-arrayexpress
Project description:The Ciona heart progenitor lineage (TVC, trunk ventral cells) is first specified by Fibroblast Growth Factor/Map Kinase (FGF/MapK) activation of the transcription factor Ets1/2 (Ets). For this analysis, B7.5 lineage cells were labeled with the Mesp-GFP reporter. In the first experiment, we targeted a dominant-negative form of the sole Ciona FGF receptor (FGFRdn) to the B7.5 lineage using the Mesp enhancer (Mesp-FGFRdn). In the second experiment, we targeted a dominant repressor form of Ets1/2 to the B7.5 lineage using the Mesp enhancer (Mesp-EtsWRPW). This construct is designed to repress Ets1/2 target gene transcription and has previously been shown to abolish TVC induction.
2012-06-05 | GSE38313 | GEO