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Role of GADD45 proteins in embryonic stem cells and their derivatives

ABSTRACT: We generated Gadd45a,b,g triple-knockout mouse embryonic stem cells and performed RNA-seq expression profiling under six different conditions of cell culture and in vitro differentiation.

ORGANISM(S): Mus musculus

PROVIDER: GSE84401 | GEO | 2019/05/31

REPOSITORIES: GEO

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Project description:Rationale: Using an ortholog candidate gene approach, we previously identified GADD45a (growth arrest and DNA damage-inducible gene 45a) as a potential novel candidate involved in ventilator-induced lung injury (VILI). Objectives: We investigated whether genetically engineered mice with GADD45a deletion were more susceptible to ventilator- or endotoxin (LPS)-induced lung injury. We employed genomic strategies to explore the mechanistic involvement of GADD45a in inflammatory lung injury. Methods: Wild-type C57Bl/6 and GADD45a-/- mice were phenotyped for lung injury following exposure to high tidal volume ventilation (VILI) or intratracheal LPS. Whole lung homogenates were utilized for gene expression studies of ventilated animals and spontaneously breathing controls. To explore the consequences of GADD45a depletion on lung vascular permeability, electrical resistance was measured using human endothelial cells (EC) transfected with small interfering RNA (siRNA) specific for GADD45a or control sequence, or with active Akt1/PKBï¡ cDNA. Results: Mice harboring deletion of GADD45a were modestly susceptible to LPS-induced injury and profoundly susceptible to VILI, demonstrating increased inflammation and increased microvascular permeability. VILI-exposed GADD45a-/- mice manifested striking neutrophilic alveolitis and increased levels of BAL protein, IgG, and inflammatory cytokines. Expression profiling revealed strong dysregulation in the B cell receptor signaling pathway in GADD45a-/- mice, with involvement of several PI3K/Akt signaling components. Akt protein and phospho-Akt were reduced in GADD45a-/- lungs. Further, human EC with reduced GADD45a (siRNA) exhibited potentiated LPS-induced barrier dysfunction, which was attenuated by overexpressing active Akt1. Conclusions: GADD45a, which modulates Akt availability, is a significant participant in modulating vascular permeability and susceptibility to VILI. Experiment Overall Design: 4 experimental groups, each with 3 mouses. Wild type control group, VILI group, GADD-/- group, GADD-/- and VILI group.

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Role of GADD45 proteins in embryonic stem cells and their derivatives

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