Similar Datasets
Project description:Cellular senescence contributes to a variety of pathologies associated with aging and is implicated as a cellular state in which cancer cells can survive treatment. Reported senolytic drug treatments act through varying molecular mechanisms, but heterogeneous efficacy across the diverse contexts of cellular senescence indicates a need for predictive biomarkers of senolytic activity. Using multi-parametric analyses of commonly reported molecular features of the senescent phenotype, we assayed a variety of models, including malignant and nonmalignant cells, using several triggers of senescence induction and found no predictive power of these traditional senescence markers to identify senolytic drug sensitivity. We sought to identify novel drug targets in senescent cells that were insensitive to frequently implemented senolytic therapies, such as Navitoclax (ABT263), using quantitative mass spectrometry to measure changes in the senescent proteome, compared to cells which acquire an acute sensitivity to ABT263 with senescence induction. Inhibition of the antioxidant GPX4 or the Bcl-2 family member MCL-1 using small molecule compounds in combination with ABT263 significantly increased the induction of apoptosis in some, but not all, previously insensitive senescent cells. We then asked if we could use BH3 profiling to measure differences in mitochondrial apoptotic priming in these models of cellular senescence and predict sensitivity to the ABT263 or the combination of dasatinib and quercetin (D+Q). We found, despite being significantly less primed for apoptosis overall, the dependence of senescent mitochondria on BCL-xL was significantly correlated to senescent cell killing by both ABT263 and D+Q, despite no significant changes in the gene or protein expression of BCL-xL. However, our data caution against broad classification of drugs as globally senolytic and instead provide impetus for context-specific senolytic targets and propose BH3 profiling as an effective predictive biomarker.
2024-12-17 | PXD054626 | Pride
Project description:The goal of this scRNA_seq was to interogate the immunosuppresive profile of infiltrating tumor immune cells in mice previously exposed to TBI and treated or not with ABT263 to kill senescent cells
2024-02-26 | GSE256486 | GEO
Project description:Purpose: The goal of this study was to characterize the kidney transcriptome of Mus musculus and Acomys cahirinus after unilateral ureteral obstruction (UUO) kidney injury. Methods: Kidney mRNA-seq profiles of 10 week old mouse and spiny mouse were generated at 2 day and 5 days after unilateral ureteral obstruction injury in triplicate, using Illumina NovaSeq 6000. The sequence reads that passed quality filters were analyzed at the transcript isoform level with Salmon, edgeR and a limma-voom pipeline in R. Results: For both Mus musculus and Acomys cahirinus kidneys, we mapped about 50 million sequence reads per sample to the mouse transcriptome and identified 20580 transcripts in kidneys of Mus musculus and 54075 transcripts in the kidneys of Acomys cahirinus. Using 1.5 fold change and FDR < 0.05, number of transcripts that are significantly different between Mus musculus samples: 3915 between normal and day 2 after UUO, 5365 between normal and day 5 after UUO. For Acomys cahirinus: 1765 between normal and day 2 after UUO, 2499 between normal and day 5 after UUO. Conclusions: Our study demonstrate there were many conserved responses to kidney injury between M. musculus and A. cahirinus despite the divergent outcomes for kidney fibrosis.
2021-09-13 | GSE168876 | GEO
Project description:Renal injury leads to chronic kidney disease for which women are not only more likely to be diagnosed with than men but also have poorer outcomes as well. We have previously shown that expression of Sprr2f, a member of the Small Proline Rich Region (Sprr) gene family, is increased several hundred fold after renal injury using a unilateral ureter obstruction (UUO) mouse model. To better understand the role of Sprr2f in renal injury, we generated a Sprr2f knockout (Sprr2f-KO) mouse model using CRISPR-Cas9 technology. To identify genes that are differentially expressed in Sprrf2f-KO mice after UUO, we performed gene expression profiling by RNA-seq on kidney tissues harvested from Sprr2f-KO mice at time 0 (n=4) and after 5 days (n=3), a time known to show dramatic changes in gene expression. Compared to day 0, expression levels of 162 genes were significantly changes with 121 up-regulated and 41 down-regulated 5 days after obstruction. Enrichment analysis using PANTHER Classification System identified 12 and 2 pathways enriched in genes that are upregulated or downregulated after UUO respectively. Eleven out of the 12 pathways enriched in the genes upregulated after UUO are related to metabolism such as drug metabolic process, consistent with a profound role of kidney as a major clearance organ of the body responsible for the elimination of many xenobiotics and prescription drugs. Interestingly, the only pathway not related to metabolism enriched in genes upregulated by UUO is oxidation-reduction, suggesting a potential role of oxidative stress in renal damage after UUO in Sprr2-KO animals. This phenotype is not observed in Sprr2f-WT animals after UUO in our previous gene expression profiling study, suggesting that Sprr2f function is sufficient to protect kidney from oxidative damage after UUO in Sprr2f-WT animals.
2020-10-13 | GSE153010 | GEO
Project description:Cellular senescence has been associated with neurodegenerative disease and clearance of senescent cells using genetic or pharmaceutical strategies (senolytics) has demonstrated beneficial effects in mouse models investigating individual disease etiologies of Alzheimer’s disease (AD). However, it has remained unclear if senescent cell clearance in a mouse model exhibiting both plaque and tau pathologies modifies the disease state (3xTg). Here, we show that treatment with senolytics (ABT263 (navitoclax) or a combination of dasatinib and quercetin (D+Q)) or transgenic removal of p16-expressing cells (via INK-ATTAC) reduced microgliosis and ameliorated both amyloid and tau pathology in 3xTg mice. Using RNA sequencing, we found evidence that synaptic dysfunction and neuroinflammation was attenuated with senescent cell removal. Unfortunately, these beneficial effects were not seen with short-term senolytic treatment in mice with more advanced disease. Overall, our results further corroborate the beneficial effects senescent cell clearance could have on AD and highlight the importance of early intervention for treatment of this debilitating disease.
2024-03-20 | GSE231332 | GEO
Project description:Chronic kidney disease is associated with progressive renal fibrosis, where perivascular cells give rise to the majority of α-SMA positive myofibroblasts. We sought to identify pericytic miRNAs that could serve as a target to decrease myofibroblast formation. We induced kidney fibrosis in FoxD1-GC;Z/Red-mice by unilateral ureteral obstruction (UUO) followed by FACS sorting of dsRed-positive FoxD1-derivative cells and miRNA profiling. MiR-132 selectively increased 21-fold during pericyte-to-myofibroblast formation whereas miR-132 was only 2.5-fold up in total kidney lysates (both in UUO and ischemia-reperfusion injury). MiR-132 silencing in UUO decreased collagen deposition (35%) and tubular apoptosis. Immunohistochemistry, western blot and qRT-PCR confirmed a similar decrease in interstitial α-SMA+ cells. Pathway analysis identified a rate-limiting role for miR-132 in myofibroblast proliferation that was confirmed in vitro. Indeed, antagomir-132 treated mice displayed a reduction in the number of proliferating, ki67+ interstitial myofibroblasts. Interestingly, this was selective for the interstitial compartment and did not impair the reparative proliferation of tubular epithelial cells, as evidenced by an increase in ki67+ epithelial cells, as well as increased (p-)RB1, Cyclin-A and decreased RASA1, p21 levels in kidney lysates. Taken together, silencing miR-132 counteracts the progression of renal fibrosis by selectively decreasing myofibroblast proliferation and could potentially serve as a novel antifibrotic therapy. Total RNA obtained from FACS sorted mouse renal FoxD1-derivatve interstitial cells from mice that were treated with antagomir-132 or scramblemir and underwent UUO (n=4)
2016-02-16 | E-GEOD-76548 | biostudies-arrayexpress
Project description:Selective removal of senescent cells, or the concept of senolytic therapy, has been proposed to be a potent strategy for overcoming age-related diseases and even reversing aging. We found that nintedanib, a tyrosine kinase inhibitor, selectively induced cell death in primary human diploid fibroblasts undergoing replicative senescence. Similar to ABT263, a well-known senolytic agent, nintedanib triggered intrinsic apoptosis in senescent cells. Additionally, at the concentration producing the senolytic effect, nintedanib arrested the cell cycle of nonsenescent cells in the G1 phase without cytotoxicity. Interestingly, compared with ABT263, nintedanib showed a different mode of activating caspase-9 in the intrinsic apoptotic pathway, in that nintedanib did not suppress the levels of Bcl-2 family proteins in senescent cells. In more detail, nintedanib suppressed the activation of the JAK2/STAT3 pathway, which caused drug-induced cell death in senescent cells. STAT3 knockdown in senescent cells also induced caspase activation. Moreover, nintedanib reduced the number of senescent cells stained based on senescence-associated β-galactosidase activity and airway resistance in a mouse model of bleomycin-induced lung fibrosis. Overall, we identified that nintedanib could be used as a new senolytic agent and that inhibiting STAT3 could be a potential approach for inducing selective cell death in senescent cells. Our findings will pave the way for expanding senolytic toolkits in response to various aging statuses and age-related diseases.
2022-09-06 | GSE210020 | GEO
Project description:In mammalian females, quiescent primordial follicles serve as the ovarian reserve and sustain normal ovarian function and egg production via folliculogenesis. The loss of primordial follicles causes ovarian aging. Cellular senescence, characterized by cell cycle arrest and production of the senescence-associated secretory phenotype (SASP), is associated with tissue aging. In the present study, we report that some quiescent primary oocytes in primordial follicles become senescent in adult mouse ovaries. The senescent primary oocytes share senescence markers characterized in senescent somatic cells. The senescent primary oocytes were observed in young adult mouse ovaries, remained at approximately 15% of the total primary oocytes during ovarian aging from 6 months to 12 months, and accumulated in aged ovaries. Administration of a senolytic drug ABT263 to 3-month-old mice reduced the percentage of senescent primary oocytes and the transcription of the SASP cytokines in the ovary. In addition, led to increased numbers of primordial and total follicles and a higher rate of oocyte maturation and female fertility. Our study provides experimental evidence that primary oocytes, a germline cell type that is arrested in meiosis, become senescent in adult mouse ovaries and that senescent cell clearance reduced primordial follicle loss and mitigated ovarian aging phenotypes.
2024-04-30 | GSE253194 | GEO
Project description:To assess the pathophysiological of genetic depletion of Yap and Wwtr1 in myofibroblasts following myocardial infarction, we utilized a Cre-lox system whereby the inducible Periostin promoter is leveraged to deplete both Yap and Wwtr1 from myofibroblasts in mice. Following myocardial infarction, myofibroblast depletion of both Yap and Wwtr1 significantly improves cardiac function after injury as compared to injured controls. Here, we have performed single cell RNA sequencing of interstitial cardiac cells 7 days post myocardial infarction to assess differentially express genes within cardiac fibroblasts and immune cell populations.
2023-02-27 | GSE204712 | GEO