Stress induced accelerated aging in mouse eye [ATAC-seq]
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE212188 | GEO | 2022/11/30
REPOSITORIES: GEO
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Project description:Aging, a universal process that affects all cells in an organism, is a major risk factor for a group of neuropathies called glaucoma, where elevated intraocular pressure is one of the known stresses affecting the tissue. Our understanding of molecular impact of aging on response to stress in retina is very limited, therefore we developed a new mouse model to approach this question experimentally. Here we show that susceptibility to response to stress increases with age and is primed on chromatin level. We demonstrate that program activated by stress caused by ocular hypertension is similar to natural aging and involves activation of inflammation and senescence. Finally, we show that multiple instances of pressure elevation cause accelerated aging of young retina as measured on transcriptional and epigenetic level and is accompanied by changes in chromatin modifications. Our data suggests that molecular mechanism of aging is regulated at the level of epigenetic activation and repression and, therefore, might be modifiable. Lastly, this work further emphasizes the importance of early diagnosis and prevention as well as age-specific management of age-related eye-diseases, including glaucoma.
2022-11-30 | GSE212187 | GEO
Project description:Aging, a universal process that affects all cells in an organism, is a major risk factor for a group of neuropathies called glaucoma, where elevated intraocular pressure is one of the known stresses affecting the tissue. Our understanding of molecular impact of aging on response to stress in retina is very limited, therefore we developed a new mouse model to approach this question experimentally. Here we show that susceptibility to response to stress increases with age and is primed on chromatin level. We demonstrate that program activated by stress caused by ocular hypertension is similar to natural aging and involves activation of inflammation and senescence. Finally, we show that multiple instances of pressure elevation cause accelerated aging of young retina as measured on transcriptional and epigenetic level and is accompanied by changes in chromatin modifications. Our data suggests that molecular mechanism of aging is regulated at the level of epigenetic activation and repression and, therefore, might be modifiable. Lastly, this work further emphasizes the importance of early diagnosis and prevention as well as age-specific management of age-related eye-diseases, including glaucoma.
2022-11-30 | GSE212186 | GEO
Project description:Purpose: The DBA/2J mouse is a model for secondary angle-closure glaucoma due to iris atrophy and pigment dispersion, which ultimately leads to increased intraocular pressure (IOP). We sought to correlate changes in retinal gene expression with glaucoma-like pathology by performing microarray analysis of retinal RNA from DBA/2J mice at 3 months before disease onset, and at 8 months, after IOP elevation. Methods: IOP was monitored monthly in DBA/2J animals by Tono-Pen and animals with normal (3 months) or elevated IOP (8 months) were identified. RNA was prepared from 3 individual retinas at each age, and the RNA was amplified and used to generate biotin-labeled probe for high density mouse Affymetrix arrays (U430.2). A subset of genes was selected for confirmation by quantitative RT-PCR using independent retina samples from DBA/2J animals at 3, 5 and 8 months of age, and compared to retinas from C57BL/6J control animals at 3 and 8 months. Results: There were changes in expression of 68 genes, with 32 genes increasing and 36 genes decreasing at 8 months versus 3 months. Upregulated genes were associated with immune response, glial activation, signaling and gene expression, while down-regulated genes included multiple crystallin genes. Significant changes in 9 upregulated genes and 2 downregulated genes were confirmed by quantitative RT-PCR, with some showing changes in expression by 5 months. Conclusions: DBA/2J retina shows evidence for glial activation and an immune-related response following IOP elevation, similar to what has been reported following acute elevation of IOP in other models. Keywords: retina, glaucoma, DBA/2J, elevated intraocular pressure
2005-11-04 | GSE3554 | GEO
Project description:Purpose: The DBA/2J mouse is a model for secondary angle-closure glaucoma due to iris atrophy and pigment dispersion, which ultimately leads to increased intraocular pressure (IOP). We sought to correlate changes in retinal gene expression with glaucoma-like pathology by performing microarray analysis of retinal RNA from DBA/2J mice at 3 months before disease onset, and at 8 months, after IOP elevation. Methods: IOP was monitored monthly in DBA/2J animals by Tono-Pen and animals with normal (3 months) or elevated IOP (8 months) were identified. RNA was prepared from 3 individual retinas at each age, and the RNA was amplified and used to generate biotin-labeled probe for high density mouse Affymetrix arrays (U430.2). A subset of genes was selected for confirmation by quantitative RT-PCR using independent retina samples from DBA/2J animals at 3, 5 and 8 months of age, and compared to retinas from C57BL/6J control animals at 3 and 8 months. Results: There were changes in expression of 68 genes, with 32 genes increasing and 36 genes decreasing at 8 months versus 3 months. Upregulated genes were associated with immune response, glial activation, signaling and gene expression, while down-regulated genes included multiple crystallin genes. Significant changes in 9 upregulated genes and 2 downregulated genes were confirmed by quantitative RT-PCR, with some showing changes in expression by 5 months. Conclusions: DBA/2J retina shows evidence for glial activation and an immune-related response following IOP elevation, similar to what has been reported following acute elevation of IOP in other models. IOP was monitored monthly in DBA/2J animals by Tono-Pen and animals with normal (3 months) or elevated IOP (8 months) were identified. RNA was prepared from 3 individual retinas at each age, and the RNA was amplified and used to generate biotin-labeled probe for high density mouse Affymetrix arrays (U430.2). A subset of genes was selected for confirmation by quantitative RT-PCR using independent retina samples from DBA/2J animals at 3, 5 and 8 months of age, and compared to retinas from C57BL/6J control animals at 3 and 8 months.
2007-12-15 | E-GEOD-3554 | biostudies-arrayexpress
Project description:To better understand the mechanistic basis of aging and its relationship with retinal degeneration, we examined gene expression changes in aging rod photoreceptors. Rod photoreceptor cell death is a feature of normal retinal aging and is accelerated in many retinal degenerative diseases, including AMD, the leading cause of untreatable adult blindness in the United States and other western countries. To our knowledge, the examination of age-related gene expression changes in a specific neuronal cell-type is novel, and it has allowed us to identify significant age-related changes with better resolution than is possible with whole retina samples. We used flow cytometry and a transgenic mouse with GFP-tagged rod photoreceptors to purify this specific cell population, and gene expression changes were evaluated at three time points using microarrays and quantitative RT-PCR. Our results suggest that aging is progressive, beginning even in young adult mice. Although rod photoreceptors are highly specialized neurons, our analyses revealed changes in consensus pathways of aging, including oxidative phosphorylation and stress responses affecting transcription and inflammation. In addition, we identified stress response processes that may be especially relevant for the aging retina and retinal diseases, such as angiogenesis and nuclear receptor signaling pathways that affect retinoid and lipid metabolism. We used flow cytometry and a transgenic mouse with GFP-tagged rod photoreceptors to purify this specific cell population, and gene expression changes were evaluated at three time points using microarrays and quantitative RT-PCR.
2010-06-14 | E-GEOD-22317 | biostudies-arrayexpress
Project description:Retina aging is the main cause of vision decline in elderly population and it is also an important risk factor for the development of degenerative and angiogenic retinal diseases. Therefore it is important to explore the mechanisms which drive retina aging. In this study, we found that retina from old-aged mice had increased mTORC1 activity. Whole transcriptome microarray expression profiling of the retina tissue among among Wild Type Control, Chx10-specific Tsc1 knockout and natural aging mice showed that the most significantly enriched Gene Ontology terms were substantially in common in knockout and aging mice compared to Control mice. we further demonstrated that the activation of mTORC1 in Chx10-expressing cells led to accelerated retina aging and degeneration, with significant functional decline measured by electroretinogram, ganglion cell senescence, microglial cell activation and the accumulation of oxidative stress and inflammatory responses. Inhibition of microglial cells by minocycline partially prevented photoreceptor cell loss and restored the electroretinogram responses. The results demonstrated that mTORC1 activation accelerated retina aging, suggested that microglial cell contributed significantly to overall retinal degeneration.
2021-06-12 | GSE177039 | GEO
Project description:The retina is a light-sensitive highly-organized tissue, which is vulnerable to aging and age-related retinal diseases. However, the effects of aging on retinal cell types including those present in neural retina and retinal pigment epithelium (RPE), as well as cell types in choroid layer remain largely unknown. Here, we established the single-cell transcriptomic atlas of the retina and adjacent choroid in young and aged non-human primates (NHPs), identifying 15 cell types with distinct gene expression signatures and finding several novel markers. Our analysis reveals that oxidative stress is a major aging feature of the cells in the neural retinal layer, whereas an enhanced inflammatory response is that of RPE and choroidal cells. We also found that the RPE cell is the cell type most susceptible to aging in retina, as evidenced by the decreased cell density as well as the highest numbers of differentially expressed genes overlapping with genes underlying aging and aging-related retinal diseases, along with aberrant cell-cell interactions with its two adjacent layers. Altogether, our study provides the roadmap for understanding retinal aging in a NHP model at single-cell resolution, enabling the identification of new diagnostic biomarkers and potential therapeutic targets for age-related human retinal disorders.
2020-10-20 | GSE113917 | GEO
Project description:The mammalian central nervous system (CNS) and its retina are susceptible to age-related patholgoies, resulting in progressive, irreversible diseases like glaucoma and age-related macular degeneration (AMD), which are increasingly prevalent with rising life expectancy. Currently, there are no targeted long-term therapies to prevent vision loss. The short lived African turquoise killifsh (Nothobranchius furzeri, GRZ-AD) is a valuable genetic model for ageing studies, displaying rapid ageing phenotypes within its four to six-month lifespan. Our investigation on the molecular consequences of ageing in the retina, employing scRNA-sequencing, shows a a comprehensive overview of the cellular heterogeneity of the killifish retina, uncovering age-related gene expression changes specific to certain retinal cell populations.
2024-08-21 | GSE255364 | GEO
Project description:Elevated intraocular pressure (IOP) is the major risk factor for glaucoma. The molecular mechanism of elevated IOP is unclear, which impedes glaucoma therapy. 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-inducible Poly-ADP-ribose Polymerase (TIPARP), a member of the PARP family, catalyses mono-ADP-ribosylation. Here we showed that TIPARP was widely expressed in the cornea, trabecular meshwork, iris, retina, optic nerve, sclera, and choroid of human eyes. The expression of TIPARP was significantly upregulated in the blood and trabecular meshwork of patients with primary open angle glaucoma compared with that of healthy controls. Transcriptome analysis revealed that the expression of genes related to extracellular matrix deposition and cell adhesion was decreased in TIPARP-upregulated human trabecular meshwork (HTM) cells. Moreover, western blot analysis showed that collagen types I and IV, fibronectin, and α-SMA were increased in TIPARP downregulated or TIPARP-inhibited HTM cells. In addition, cross-linked actin networks were produced, and vinculin was upregulated in these cells. Subconjunctival injection of the TIPARP inhibitor RBN-2397 increased the IOP in Sprague–Dawley rats. Therefore, we identified TIPARP as a regulator of IOP through modulation of extracellular matrix and cell cytoskeleton proteins in HTM cells. These results indicate that TIPARP is a potential therapeutic target for ocular hypertension and glaucoma.
2022-12-28 | GSE218153 | GEO
Project description:Glaucoma is a neurodegenerative disease in which vision is lost as a result of the apoptosis of retinal ganglion cells. When the trabecular meshwork cells, that regulate aqueous humor outflow, are stressed as they are in some forms of glaucoma, they considerably up-regulated secretion of a protein called myocilin into the aqueous. The function of this protein is unclear; but since some aqueous humor flows to the posterior of the eye, the effects of myocilin will also be felt by the retinal cells. We have a transgenic mouse that secretes large amounts of myocilin into aqueous humor. In these mice, there is a deposition of myocilin on membranes of certain cells suggesting myocilin might have some signaling functions. This signaling function could explain why stresses that increase intraocular pressures can increase the likelihood for glaucoma, cause the myocilin to be secreted at very high levels by the trabecular meshwork. Myocilin may be important in treating glaucoma. This experiment will determine if myocilin is altering gene expression in the retina. The results should show variations in expression levels and will give us some indication of the pathways that are important to preserve retinal ganglion cells after a diagnosis of glaucoma. Our hypothesis is that myocilin is acting like a signaling protein in the eye. It acts not only in the anterior segment but also in retina as a result of the flow of some aqueous to the back of the eye. This signaling function is protective to certain ocular cells. This function of myocilin may influence cells in the retina and may counter the apoptotic signals in the retinal ganglion cells that occur during glaucoma. Retinas from transgenic mice and from mice of the same strain that do not have the transgene will be dissected. The mice will be three weeks of age. Because of the small size of the retina, samples will be pooled to obtain the RNA necessary to run the microarray. Three control and three transgenic samples will be run and compared with each other. We have data indicating that myocilin is at high levels in the aqueous humor of the transgenic animals.
2008-06-11 | E-GEOD-1835 | biostudies-arrayexpress