Early removal of senescent cells protects retinal ganglion cells loss in experimental ocular hypertension
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE141725 | GEO | 2020/12/01
REPOSITORIES: GEO
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Project description:The goal of this study is to identify the senescent cells expressing high level of p16Ink4a (p16Ink4a Hi) in GBMs and characterize their action on the tumor microenvironment at an early timepoint. We introduced the p16-3MR transgene in the GBM mouse model to selectively delete p16Ink4a Hi senescent cells upon ganciclovir (GCV) injection. We compared p16-3MR+GCV to WT+GCV control GBMs that were harvested 7 days after the last GCV injection.
2022-12-15 | GSE198439 | GEO
Project description:The goal of this study is to identify the senescent cells expressing high level of p16Ink4a (p16Ink4a Hi) in GBMs, at an early timepoint. We introduced the p16-3MR transgene in the GBM mouse model to selectively delete p16Ink4a Hi senescent cells upon ganciclovir (GCV) injection. We compared two p16-3MR+GCV to two WT+GCV control GBMs that were harvested 7 days after the last GCV injection. p16Ink4a Hi senescent cells were a subset of malignant cells, mostly grouped in the astrocyte cluster and to a lesser extend in the NP-like cluster. We also found that p16Ink4a Hi senescent cells deletion modifies the cell state of malignant cells and modulates the tumor microenvironment. This study allowed us to define a GBM senescence signature.
2022-12-15 | GSE168038 | GEO
Project description:GBM mouse model: The goal of this study is to compare the transcriptomic landscape at the endpoint of GBMs upon senescent cells deletion. We introduced the p16-3MR transgene in the GBM mouse model to selectively delete senescent cells expressing high level of p16Ink4a (p16Ink4a Hi) upon ganciclovir (GCV) injection. We compared p16-3MR+GCV GBMs to two control conditions, either WT+GCV or p16-3MR+GCV. We showed a slight decreased of p16Ink4a transcripts in p16-3MR+GCV compared to WT+GCV GBMs and GSEA demonstrated significant down-regulation of senescence pathways in p16-3MR+GCV GBMs compared to control GBMs. GBM-derived organoids: We used a mouse GBM-derived organoids model to further explore the function of Nrf2, that we identified as one potential trigger of the pro-tumoral action of p16Ink4a Hi malignant cells. We compared GBM-derived organoids treated with the senolytic ABT263 (Navitoclax; inhibitor of the anti-apoptotic proteins Blcl2 and BCL-xL) or vehicle (vhc) after 14 days in culture. We validated ABT263 efficacy via the significant downregulation of the expression of p16Ink4a, p15Ink4b and p21Cip1 senescent markers. We further identified upon senolytic treatment, downregulated genes encoding for SASP. Importantly, GSEA revealed a significant downregulation of Nrf2 pathway upon senolytic treatment.
2022-12-15 | GSE168037 | GEO
Project description:Goals of the study: 1. Assess the gene expression profile in rat RGC after experimental IOP elevation to elucidate the molecular mechanisms of RGC death. 2. Identify potentially novel genes and pathways that may contribute to RGC death in glaucoma. Background: Glaucoma is a neurodegenerative disease characterized by the slow, progressive degeneration of RGC. Elevated IOP is the biggest risk factor for developing glaucoma, loss of RGC and optic nerve atrophy. The pathophysiology of glaucomatous neurodegeneration is not fully understood. It is now clear that RGC die by apoptosis in glaucoma. However, what triggers the apoptosis is still unknown. So far, several gene expression studies have been performed on the retina as a whole. These studies revealed up and downregulation of many genes in response to elevated IOP and optic nerve transection. However, the retina is a complex tissue composed of neuronal, glial and vascular cell types. The RGCs only comprise 5% or less of retinal cells. The gene expression profiles from whole retina can not represent of RGC gene expression. In the current study, we sought to investigate the whole genome regulation of the RGCs in glaucoma. The study was carried out in 3 adult male Brown Norway rats with experimental glaucoma. An equal number of RGCs were captured from normal eyes and eyes with elevated IOP. Gene expression in the glaucomatous RGC was compared with that in the fellow RGC by using Affymetrix Gene chip.
2010-10-01 | E-GEOD-12596 | biostudies-arrayexpress
Project description:Purpose: The optic nerve head (ONH) is the likely site of initial damage in the glaucomatous eye. Despite the recognition of elevated intraocular pressure (IOP) as a leading risk factor for the development of glaucoma, ocular hypertension (OHT) eyes displaying consistently elevated IOP do not experience ONH damage. This study aims to identify global gene expression variations in glaucomatous ONHs and their relationship to those identified in OHT derived ONHs in order to improve our understanding of IOP-induced ONH damage. Methods: (N=6) ONHs were collected from clinically confirmed glaucoma, OHT and age-matched control donor eyes. Total RNA extracted from ONHs was reverse transcribed and assayed using the Affymetrix Human Exon 1.0 ST array. Differentially expressed genes in glaucoma versus control and OHT derived ONHs were identified using an ANOVA analysis with a 1.25 fold change limit and P-value < 0.05. Quantitative RT-PCR was performed to validate selected differentially expressed genes. Results: Microarray analysis revealed 149 under under-expressed genes in POAG versus control ONHs, many of which are involved in ion transport, axonogenesis and macromolecule catabolic processes. 297 genes were over expressed in OHT versus glaucoma derived ONHs. Mediators of oxidation-reduction and chemical homeostasis were among the most prominent gene groups identified. The over expression of prostaglandin-endoperoxide synthase 2, integrin, beta-like 1 and fibulin 5 in glaucomatous ONHs was confirmed by qRT-PCR. Conclusions: Our data demonstrates marked alteration in global gene expression patterns in the glaucomatous ONH, likely due to extensive tissue injury. The observed overlapping of several differentially expressed genes in glaucoma and OHT derived ONHs suggests the induction of common mechanisms in response to elevated IOP. Preferential over-expression of certain gene groups in OHT but not glaucoma derived ONHs may confer possible protection against IOP-induced ONH damage, which remains to be investigated in future studies. (N=6) Glaucoma, ocular hypertension and age-matched control ONHs were assayed to investigate and compare global gene expression patterns in each sample group.
2013-09-27 | E-GEOD-45570 | biostudies-arrayexpress
Project description:Intraocular pressure was elevated through episkleral vein occlusion by thermic cauterization of SD rats. Animals were further sacrificed after different periods of elevated IOP and the retinal proteins were investigated for alterations regarding the relative protein level in this experimental model of glaucoma.
2017-04-11 | PXD005258 | Pride
Project description:Intraocular pressure was elevated through episkleral vein occlusion by thermic cauterization of SD rats. Animals were further sacrificed after different periods of elevated IOP and the retinal proteins were investigated for alterations regarding the relative protein level in this experimental model of glaucoma.
2017-11-28 | MSV000081757 | MassIVE
Project description:Purpose: The optic nerve head (ONH) is the likely site of initial damage in the glaucomatous eye. Despite the recognition of elevated intraocular pressure (IOP) as a leading risk factor for the development of glaucoma, ocular hypertension (OHT) eyes displaying consistently elevated IOP do not experience ONH damage. This study aims to identify global gene expression variations in glaucomatous ONHs and their relationship to those identified in OHT derived ONHs in order to improve our understanding of IOP-induced ONH damage. Methods: (N=6) ONHs were collected from clinically confirmed glaucoma, OHT and age-matched control donor eyes. Total RNA extracted from ONHs was reverse transcribed and assayed using the Affymetrix Human Exon 1.0 ST array. Differentially expressed genes in glaucoma versus control and OHT derived ONHs were identified using an ANOVA analysis with a 1.25 fold change limit and P-value < 0.05. Quantitative RT-PCR was performed to validate selected differentially expressed genes. Results: Microarray analysis revealed 149 under under-expressed genes in POAG versus control ONHs, many of which are involved in ion transport, axonogenesis and macromolecule catabolic processes. 297 genes were over expressed in OHT versus glaucoma derived ONHs. Mediators of oxidation-reduction and chemical homeostasis were among the most prominent gene groups identified. The over expression of prostaglandin-endoperoxide synthase 2, integrin, beta-like 1 and fibulin 5 in glaucomatous ONHs was confirmed by qRT-PCR. Conclusions: Our data demonstrates marked alteration in global gene expression patterns in the glaucomatous ONH, likely due to extensive tissue injury. The observed overlapping of several differentially expressed genes in glaucoma and OHT derived ONHs suggests the induction of common mechanisms in response to elevated IOP. Preferential over-expression of certain gene groups in OHT but not glaucoma derived ONHs may confer possible protection against IOP-induced ONH damage, which remains to be investigated in future studies.
2013-09-27 | GSE45570 | GEO
Project description:Goals of the study: 1. Assess the gene expression profile in rat RGC after experimental IOP elevation to elucidate the molecular mechanisms of RGC death. 2. Identify potentially novel genes and pathways that may contribute to RGC death in glaucoma. Background: Glaucoma is a neurodegenerative disease characterized by the slow, progressive degeneration of RGC. Elevated IOP is the biggest risk factor for developing glaucoma, loss of RGC and optic nerve atrophy. The pathophysiology of glaucomatous neurodegeneration is not fully understood. It is now clear that RGC die by apoptosis in glaucoma. However, what triggers the apoptosis is still unknown. So far, several gene expression studies have been performed on the retina as a whole. These studies revealed up and downregulation of many genes in response to elevated IOP and optic nerve transection. However, the retina is a complex tissue composed of neuronal, glial and vascular cell types. The RGCs only comprise 5% or less of retinal cells. The gene expression profiles from whole retina can not represent of RGC gene expression. In the current study, we sought to investigate the whole genome regulation of the RGCs in glaucoma.
2010-10-01 | GSE12596 | GEO
Project description:Increased intraocular pressure (IOP) represents a major risk factor for glaucoma, a prevalent eye disease characterized by death of retinal ganglion cells that carry information from the eye to the brain; lowering IOP is the only proven treatment strategy to delay disease progression. The main determinant of IOP is the equilibrium between production and drainage of aqueous humor, with compromised drainage generally viewed as the primary contributor to dangerous IOP elevations. Drainage occurs through two pathways in the anterior segment of the eye, called conventional and uveoscleral. To gain insights into the cell types that comprise these pathways, we used high-throughput single cell RNA sequencing (scRNA-seq). From ~24,000 single cell transcriptomes, we identified 19 cell types with molecular markers for each and used histological methods to localize each type. We then performed similar analyses on four organisms used for experimental studies of IOP dynamics and glaucoma: cynomolgus macaque (Macaca fascicularis), rhesus macaque (Macaca mulatta), pig (Sus scrofa) and mouse (Mus musculus). Many human cell types had counterparts in these models, but differences in cell types and gene expression were evident. Finally, we identified the cell types that express genes implicated in glaucoma in all five species. Together, our results provide foundations for investigating the pathogenesis of glaucoma, and for using model systems to assess mechanisms and potential interventions.
2020-05-19 | GSE148374 | GEO