Targeting p16-induced Senescence Prevents Cigarette Smoke-Induced Emphysema by Promoting IGF1/Akt1 Signaling in mice
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PROVIDER: PRJNA551293 | ENA |
REPOSITORIES: ENA
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Project description:Increased IGF1 signaling in p16 -/- lungs
2019-06-27 | GSE133380 | GEO
Project description:Senescence is a mechanism associated with aging that alters tissue regeneration by depleting the stem cell pool. Chronic obstructive pulmonary disease (COPD) displays hallmarks of senescence, including a diminished stem cell population. DNA damage from cigarette smoke (CS) induces senescence via the p16 pathway. This study evaluated the contribution of p16 to CS-associated lung pathologies. p16 expression was prominent in human COPD lungs compared with normal subjects. CS induces impaired pulmonary function, emphysema, and increased alveolar epithelial cell (AECII) senescence in wild-type mice, whereas CS-exposed p16-/- mice exhibit normal pulmonary function, reduced emphysema, diminished AECII senescence, and increased pro-growth IGF1 signaling, suggesting that improved lung function in p16-/- mice was due to increased alveolar progenitor cell proliferation. In conclusion, our study suggests that targeting senescence may facilitate alveolar regeneration in COPD emphysema by promoting IGF1 proliferative signaling.
| S-EPMC6689060 | biostudies-literature
Project description:Transcriptional profiling of p16-induced senescent human diploid fibroblasts compared with proliferating cells. TIG-3 ER-p16 cells (primary normal human diploid fibroblasts expressing a 4-hydroxytamoxifen(4-OHT) regulatable form of human p16) were cultured for 7 days with or without 4-OHT. Total RNA was isolated using TRIzol reagent and were analyzed using the hum
2014-04-10 | E-GEOD-49863 | biostudies-arrayexpress
Project description:Chronic obstructive pulmonary disease (COPD) is a complex pulmonary disorder primarily induced by cigarette smoking, and characterized by persistent airflow limitation. The mouse represents an important model for studying COPD pathologies such as lung emphysema. In this respect, a number of mechanistic studies have been performed, however the approaches were mostly focused on single gene analysis or characterization of cellular, inflammatory or histopathological changes without attempting a more comprehensive interpretation. In the present study we aimed at applying systems biology approach to identify genome-wide molecular mechanisms indicative of cigarette smoke (CS)-induced lung emphysema. The lung transcriptomes of five mouse models (C57BL/6, ApoE-/-, A/J, CD1, and Nrf2-/-), that are known to be susceptible to CS-induced emphysema development, were analyzed following prolonged (5-6 months) CS exposure. The investigation resulted in the confirmation of many existing mechanistic explanations underlying smoke-induced lung emphysema, including increased transcriptional activity of NF-?B, and increased levels of TNF-a, IFN-g, and IL-1b. More importantly, we predicted mechanisms without currently well-documented roles, including increased transcriptional activity of PU.1, STAT1, C/EBP, FOXM1, YY1 and N-cor, and increased IL-17 cytokine expression, and reduced protein expression of ITGB6 and CFTR. We also corroborated, by using targeted proteomic approaches, several predictions such as reduced expression of ITGB6 and increased expression of BRCA1, C/EBPs, PU.1, TNF-a, IL-1b or CSF2. We believe this study will provide more insights into better understanding of CS-induced molecular processes underlying emphysema development in mice that may eventually be relevant in humans.
2014-11-28 | E-MTAB-2756 | biostudies-arrayexpress
Project description:Patients with chronic obstructive pulmonary disease (COPD) having higher blood eosinophil levels exhibit worse lung function and more severe emphysema, implying the potential role of eosinophils in emphysema development. However, the specific mechanism underlying eosinophil-mediated emphysema development is not fully elucidated. In this study, single-cell RNA sequencing was used to identify eosinophil subgroups in mouse models of asthma and emphysema and analyze their functions. Analysis of the accumulated eosinophils revealed differential transcriptomes between the mouse lungs of elastase-induced emphysema and ovalbumin-induced asthma., Eosinophil depletion alleviated elastase-induced emphysema. Notably, eosinophil-derived cathepsin L (CTSL) degraded the extracellular matrix (ECM), causing emphysema in the pulmonary tissue. Eosinophils were positively correlated with serum CTSL levels, which were increased in patients with emphysema than in those without emphysema. Collectively, these results suggest that CTSL expression in eosinophils plays an important role in ECM degradation and remodeling and is related to emphysema in patients with COPD. Therefore, eosinophil-derived CTSL may serve as a potential therapeutic target for patients with emphysema.
2023-10-17 | GSE237749 | GEO
Project description:Transcriptional profiling of p16-induced senescent human diploid fibroblasts compared with proliferating cells.
2014-04-10 | GSE49863 | GEO
Project description:MicroRNAs regulated by lipopolysaccharide (LPS) target genes that contribute to the inflammatory phenotype. Here we showed that the protein kinase Akt1, which is activated by LPS, positively regulated miRNAs let-7e, miR-181c but negatively regulated miR-155 and miR-125b. In silico analyses and transfection studies revealed that let-7e repressed Toll-like receptor 4 (TLR4) whereas miR-155 repressed SOCS1, two proteins critical for LPS-driven TLR signalling, which regulate endotoxin sensitivity and tolerance. As a result, Akt1-/- macrophages exhibited increased responsiveness to LPS in culture and Akt1-/- mice did not develop endotoxin tolerance in vivo. Overexpression of let-7e and suppression of miR-155 in Akt1-/- macrophages restored sensitivity and tolerance to LPS in culture and in animals. These results indicate that Akt1 regulates the response of macrophages to LPS by controlling miRNA expression. The data deposited here contain the entire analysis of miRNA profile of Akt1+/+ and Akt1-/- thioglycollate elicited peritoneal macrophages following stimulation with LPS for 3 hours in culture.
2009-08-21 | GSE17421 | GEO
Project description:PTPRD is a tumor suppressor of glioma that is frequently co-deleted with CDKN2A/p16. We show that Ptprd and p16 cooperate to promote gliomagenesis in the RCAS PDGFB / Nestin tv-A glioma mouse model. We found unique gene expression changes within tumor cells of Ptprd+/-p16-/- vs. Ptprd+/+p16-/- and Ptprd-/-p16-/- tumor cells. Neonatal mice were injected with RCAS PDGFB GFP. At symptoms, or at 12 weeks post injection, GFP+DAPI- tumor cells were sorted for RNA extraction and hybridization on Affymetrix microarrays. The mouse strain used was a mixed background of C57/BL6 and FVB/N. Ptprd mice were from Uetani et al. 2000 and p16/Nestin-tvA mice were from Tchouganouva et al. 2007.
2014-06-02 | E-GEOD-55061 | biostudies-arrayexpress
Project description:Dysregulated myogenesis and autophagy in genetically induced pulmonary emphysema
| PRJNA747279 | ENA
Project description:MicroRNAs regulated by lipopolysaccharide (LPS) target genes that contribute to the inflammatory phenotype. Here we showed that the protein kinase Akt1, which is activated by LPS, positively regulated miRNAs let-7e, miR-181c but negatively regulated miR-155 and miR-125b. In silico analyses and transfection studies revealed that let-7e repressed Toll-like receptor 4 (TLR4) whereas miR-155 repressed SOCS1, two proteins critical for LPS-driven TLR signalling, which regulate endotoxin sensitivity and tolerance. As a result, Akt1-/- macrophages exhibited increased responsiveness to LPS in culture and Akt1-/- mice did not develop endotoxin tolerance in vivo. Overexpression of let-7e and suppression of miR-155 in Akt1-/- macrophages restored sensitivity and tolerance to LPS in culture and in animals. These results indicate that Akt1 regulates the response of macrophages to LPS by controlling miRNA expression. The data deposited here contain the entire analysis of miRNA profile of Akt1+/+ and Akt1-/- thioglycollate elicited peritoneal macrophages following stimulation with LPS for 3 hours in culture. Thioglycollate elicited macrophages were cultured in complete DMEM medium, stimulated with LPS for 3 hours and RNA was extracted. Samples were analyzed using Taq-man PCR miRNA arrays (Dana Farber microarray Facility).
2009-08-21 | E-GEOD-17421 | biostudies-arrayexpress