Intermittent fasting alleviates photoreceptor degeneration and retina inflammation in oxidative stress-induced model of Age-Related Macular Degeneration
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ABSTRACT:
PROVIDER: PRJNA1133187 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR29746514_1.fastq.gz | Fastqsanger.gz | |||
| SRR29746514_2.fastq.gz | Fastqsanger.gz | |||
| SRR29746515_1.fastq.gz | Fastqsanger.gz | |||
| SRR29746515_2.fastq.gz | Fastqsanger.gz | |||
| SRR29746516_1.fastq.gz | Fastqsanger.gz |
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Project description:Age-related macular degeneration (AMD), a prevalent neurodegenerative disorder, remains the leading cause of vision loss among the elderly population. Despite the urgent need, effective treatments or preventive strategies for AMD are not available. Recent studies have highlighted the potential neuroprotective benefits of intermittent fasting (IF) in several models of aging and age-associated disorders. However, its efficacy in AMD has not been established. Our current research reveals that IF alleviated neurodegeneration by reducing RPE and photoreceptor cell damage in an oxidative stress-induced mouse model of AMD. The assessment of visual capabilities in mice through optomotor response (OMR) tests indicates that IF markedly preserved visual function in NaIO3-treated mice. To understand the mechanism by which IF exerts its protective effects, we performed transcriptome analyses and found that IF can counteract numerous transcriptional alterations induced by NaIO3, predominantly affecting genes involved in photoreceptor structure, inflammatory pathways and reactive oxygen species (ROS) process. Further, we demonstrated through multiple experiments that IF could effectively reduce ROS levels and restraining the hyperactivation of microglia and Müller cells within the RPE and retina. Moreover, we explored the initiation of IF at a later stage in an individual's lifespan and found that benefits were also obtained in the AMD model. Collectively, this study indicates IF exerts neuroprotective effects by reducing ROS production and inflammation in the retina, and is expected to become a new strategy for retinal degenerative diseases caused by oxidative damage, incluiding AMD.
2024-07-09 | GSE271791 | GEO
Project description:Primary and secondary cone photoreceptor cell death in retinal degenerative diseases, including age-related macular degeneration and retinitis pigmentosa, leads to severe vision impairment and blindness. Regardless of the fact that protection of cone photoreceptor cells under stress conditions, such as retinal degenerative diseases, is crucial for maintaining vision, the underlying molecular mechanisms are unclear. Here, we investigated the function of the deubiquitinase Otud7b/Cezanne in the retina. We identified that Otud7b is predominantly expressed in photoreceptor cells in the mouse retina. While the ablation of Otud7b did not cause a significant defect in development and maturation of the mouse retina, Otud7b‒/‒ mice subjected to light-induced damage, which is one of the dry age-related macular degeneration models, exhibited increased cone photoreceptor degeneration. In addition, Otud7b deficiency in Mak‒/‒ mice, a retinitis pigmentosa mouse model, resulted in further cone photoreceptor degeneration. Moreover, neuronal cells deficient in Otud7b were susceptible to serum starvation, resulting in cell death. We found that NF-κB activity is increased in the Otud7b‒/‒ retinas exposed to light by RNA-sequencing analysis. Luciferase reporter assay also demonstrated increased NF-κB activation in Otud7b-deficient neuronal cells under stress. The neuronal cell death resulting from Otud7b deficiency was suppressed through the inhibition of NF-κB. Furthermore, we observed that inhibition of NF-κB attenuated cone photoreceptor degeneration in the light-exposed Otud7b‒/‒ retina. Together, the current study suggests that Otud7b deubiquitinase protects cone photoreceptor cells under stress conditions by modulating the NF-κB activity.
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Project description:Age-related macular degeneration (AMD) is a chronic, multifactorial disorder and a leading cause of blindness in the elderly. Characterized by progressive photoreceptor degeneration in the central retina, disease progression involves epigenetic changes in chromatin accessibility resulting from environmental exposures and chronic stress. Here, we report that a photosensitive mouse model of acute stress-induced photoreceptor degeneration recapitulates the epigenetic hallmarks of human AMD. Global epigenomic profiling by assay for transposase-accessible chromatin using sequencing (ATAC-Seq) revealed an association between decreased chromatin accessibility and stress-induced photoreceptor cell death in our mouse model. The epigenomic changes induced by light damage include reduced euchromatin and increased heterochromatin abundance, resulting in transcriptional and translational dysregulation that ultimately drives photoreceptor apoptosis and an inflammatory reactive gliosis in the retina. Through our findings, we identified key histone-modifying enzymes that contribute to the observed changes in global chromatin accessibility. Moreover, pharmacological inhibition of histone deacetylase 11 (HDAC11) and suppressor of variegation 3-9 homolog 2 (SUV39H2) ameliorated light damage in our mouse model, supporting a causal link between decreased chromatin accessibility and photoreceptor degeneration, thereby representing a potential new therapeutic strategy to combat AMD.
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Project description:This SuperSeries is composed of the following subset Series: GSE28002: Gene expression of the whole mouse eye GSE28032: Epigenetic Regulation of IL17RC in Age-related Macular Degeneration (MeDIP-chip) Refer to individual Series
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Project description:Genome-wide association studies have uncovered mostly non-coding variants at over 60 age- related macular degeneration (AMD) susceptibility loci. To ascertain the target gene at the PILRB/PILRA locus, we used a CRISPR strategy to produce germline deletions in the mouse paired immunoglobin-like type 2 receptor (Pilr) genes that encode highly related activating (PILRB) and inhibitory (PILRA) receptors. We show that a combined loss of Pilrb1 and Pilrb2, but not Pilra, leads to an early but relatively stationary defect in photoreceptor function without any apparent change in other retinal cells. PILRB immunostaining is specifically detected at the proximal part of photoreceptor outer segment. Reduced expression of select calcium-regulated phototransduction and synapse-associated proteins, including GCAP1 and 2, PDE6B, AIPL1, PSD95, and CTBP1, indicate dysregulation of calcium homeostasis as a possible mechanism of retinal phenotype in Pilrb1/2 -/- mice. Our studies suggest an association of PILRB, and not PILRA, with AMD pathogenesis.
2024-10-10 | GSE264349 | GEO
Project description:Age-related macular degeneration has a strong epidemiological association with cardiovascular disease. One pathogenic hypothesis that applies to both diseases is the concept of an abnormal cellular response to injury resulting in a disease phenotype. It has been hypothesized that this phenotype is also present in dermal fibroblasts. This study tests this hypothesis by examination of the expression profiles of fibroblasts obtained from diseased patients and subjected to sublethal cell injury. Keywords: other
2004-09-02 | GSE1719 | GEO
Project description:Age-related macular degeneration (AMD) is a common, blinding disease of the elderly in which macular photoreceptor cells, retinal pigment epithelium, and choriocapillaris endothelial cells ultimately degenerate. Recent studies have found that degeneration of the choriocapillaris occurs early in this disease and that this endothelial cell dropout is concomitant with increased deposition of the complement membrane attack complex (MAC) at the choroidal endothelium. However, the impact of MAC injury to choroidal endothelial cells is poorly understood. To model this event in vitro, and to study the downstream consequences of MAC injury, endothelial cells were exposed to complement from human serum, compared to heat inactivated serum which lacks complement components. Cells exposed to complement components in human serum showed increased labeling with antibodies directed against the MAC, time and dose dependent cell death as assessed by lactate dehydrogenase assay, and increased permeability. RNA-Seq analysis following complement injury revealed increased expression of genes associated with angiogenesis including matrix metalloproteases (MMPs) 3 and 9, and VEGF-A. The MAC-induced increase in MMP9 RNA expression was validated using C5 depleted serum compared to C5 reconstitited serum. Increased levels of MMP9 were also determined using Western blot and zymography. These data suggest that, in addition to cell lysis, complement attack on choroidal endothelial cells promotes an angiogenic phenotype in surviving cells. RNA-Seq of RF/6A (cultured choroidal endothelial cells from Rhesus macaque) treated with either 50% heat-inactivated human serum ([CONTROL], n=3) or 50% normal human serum (active complement membrane attack complex [MAC], n=3)
2015-11-04 | E-GEOD-70806 | biostudies-arrayexpress
Project description:Due to commonalities in pathophysiology, age-related macular degeneration represents a uniquely accessible model to investigate therapies for neurodegenerative diseases, leading us to examine whether pathways of disease progression are shared across neurodegenerative conditions. Here we use single-nucleus RNA sequencing to profile lesions from 17 retinas with age-related macular degeneration and controls. We create a machine learning pipeline based on recent advances in data geometry and topology and identify activated glial populations enriched in the early phase of disease. Examining single-cell data from Alzheimer’s disease and progressive multiple sclerosis with our pipeline, we find a similar glial activation profile enriched in the early phase of these neurodegenerative diseases. In late-stage age-related macular degeneration, we identify a microglia-to-astrocyte signaling axis mediated by interleukin-1beta which drives angiogenesis characteristic of disease pathogenesis. Thus, due to shared glial states, the retina provides a system for investigating therapeutic approaches in neurodegenerative diseases.
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Project description:Illumina Infinium HumanMethylation450 BeadChip data from genomic DNA of retinal pigment epithelium from Age-related Macular Degeneration patients or age-matched controls.
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