Injectable anti-inflammatory supramolecular nanofiber hydrogel to promote ranibizumab therapy in age-related macular degeneration treatment
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE165702 | GEO | 2024/01/28
REPOSITORIES: GEO
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Project description:Age-related macular degeneration (AMD) is a global leading cause of visual impairment in older populations. ‘Wet’ AMD, the most common subtype of this disease, occurs when pathological angiogenesis infiltrates the subretinal space (choroidal neovascularization), causing hemorrhage and retinal damage. Gold standard anti-vascular endothelial growth factor (VEGF) treatment is an effective therapy, but the long-term prevention of visual decline has not been as successful. This warrants the need to elucidate potential VEGF-independent pathways. We generated blood out-growth endothelial cells (BOECs) from wet AMD and normal control subjects, then induced angiogenic sprouting of BOECs using a fibrin gel bead assay. To deconvolute endothelial heterogeneity, we performed single-cell transcriptomic analysis on the sprouting BOECs, revealing a spectrum of cell states. Our wet AMD BOECs share common pathways with choroidal neovascularization such as extracellular matrix remodeling that promoted proangiogenic phenotype, and our ‘activated’ BOEC subpopulation demonstrated proinflammatory hallmarks, resembling the tip-like cells in vivo. We uncovered new molecular insights that pathological angiogenesis in wet AMD BOECs could also be driven by interleukin signaling and amino acid metabolism. A web-based visualization of the sprouting BOEC single-cell transcriptome (https://christinecheunglab.shinyapps.io/human_wet_AMD_sprouting/) has been created to facilitate further discovery research.
2022-11-02 | GSE213933 | GEO
Project description:To explore whether IL-4 could exert a novel protective role for RPE damage and attenuate the pathogenesis of dry age-related macular degeneration (AMD), we established a retinal degeneration model of dry AMD by intravenous injection of NaIO3, and explored the treatment effects of intravitreal IL-4 injection. We found exogenous IL-4 protected against retinal degeneration characterized by well-preserved structures and improved retinal function. The RNA-seq analysis revealed that IL-4 treatment suppressed the essential oxidative and pro-inflammatory pathways in the degenerative retina. IL-4 induced the expression of IL-4Rα and Nrf2 for anti-oxidative defense in vivo and in vitro. Our data provides evidences that IL-4 can be a useful neuroprotective agent against retinal degeneration due to its antioxidant and anti-inflammatory property through Nrf2 activation. The IL-4/IL-4Rα-Nrf2 axis maybe the potential targets for the development of novel therapies for dry AMD.
2022-12-17 | GSE193808 | GEO
Project description:Neovascularization contributes to multiple visual disorders including age-related macular degeneration (AMD). Current therapies for treating ocular angiogenesis are centered on the inhibition of vascular endothelial growth factor (VEGF). While clinically effective, some AMD patients are refractory or develop resistance to anti-VEGF and concerns of increased risks of developing geographic atrophy following long-term treatment have been raised. Identification of alternative pathways to inhibit pathological angiogenesis is thus important. We have identified a novel inhibitor of angiogenesis, COCO/DAND5, a member of the Cerberus-related DAN family. We demonstrate that COCO inhibits sprouting, migration and cellular proliferation of cultured endothelial cells. Intravitreal injections of COCO inhibited retinal vascularization during development and in models of retinopathy of prematurity and AMD. COCO equally abrogated angiogenesis in choroid explants and in a model of choroidal neovascularization. Mechanistically, COCO inhibited the expression of TGFβ and BMP pathwaysand altered ATP production, glucose uptake and redox balance of endothelial cells. Together, these data show that COCO is an inhibitor of retinal and choroidal angiogenesis, possibly representing a therapeutic option for the treatment of neovascular ocular diseases.
2020-12-22 | GSE160099 | GEO
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:Age-related macular degeneration (AMD) is a leading cause of blindness among the elderly. Using clinical samples and knockout mice, we reported that the m1A eraser ALKBH3 reshaped retinal metabolism to promote AMD. In retinal pigment epithelium (RPE), the dm1ACRISPR system demonstrated that ALKBH3 demethylated the glycolytic enzyme HK2 to activate anaerobic glycolysis, producing excessive lactate. The lactate promoted histone lactylation at H3K18, which in turn bound to ALKBH3 to amplify its transcription, establishing a positive feedback loop. The ALKBH3 inhibitor HUHS015 disrupted this loop, effectively mitigating RPE degeneration. Furthermore, ALKBH3 directly targeted the pro-angiogenic factor VEGFA to modulate the metabolic cross-talk between RPE and choroidal capillaries, thus promoting choroidal neovascularization (CNV). HUHS015 inhibited CNV synergistically with the anti-VEGF drug Aflibercept. Our study provides critical insights into the molecular mechanisms and metabolic events facilitating the progression from RPE degeneration to CNV in AMD, laying the groundwork for new treatments of AMD.
2024-08-14 | GSE274399 | GEO
Project description:Choroidal neovascularization (CNV) and the resulting retinal angiogenesis are pathological hallmarks of wet Age-related macular degeneration (AMD). The pathogenesis of CNV is not fully understood, but accumulated evidence has suggested the role of inflammation in the early stage of CNV. To better understand the molecular landscape during the early stage, we performed RNA-Seq and mass spectrometry-based proteomic analysis in the retina of the laser-induced CNV mouse model. Both transcriptomic and proteomic data showed dramatic activation of inflammatory response 3 days post photocoagulation. Integrative analysis suggested a moderate correlation between RNA-Seq and mass spec. Up-regulation of angiogenic factor, basic fibroblast growth factor-2 (Fgf-2), but not vascular endothelial growth factor (Vegf) was observed at both RNA and protein levels, highlighting Fgf-2 as a biomarker and potential therapeutic target during the early stage of CNV. In addition, enrichment analysis indicated a large overlap of inflammation-related genes and pathways at both levels. We also compared our findings with human retinal RNA-Seq data from AMD patients and controls. By using a multi-omics and comparative approach, our findings demonstrate the molecular landscape during the inflammatory stage of mouse CNV and provided new insight into the translation from the mouse model to understanding human AMD and its potential intervention and therapies.
2024-01-17 | GSE207171 | GEO
Project description:Background Age-related macular degeneration (AMD) is the leading cause of irreversible blindness in the elderly population worldwide. Recent studies have demonstrated strong genetic associations between AMD and single nucleotide polymorphisms (SNPs) within genes such as CFH and HTRA1. However, we have identified monozygotic twins discordant for AMD phenotypes (one with disease, the other without disease), suggesting that an epigenetic mechanism may also contribute to the pathogenesis of AMD. Methods We identified two twin pairs with phenotypic discordance of AMD. We obtained genomic DNA from their peripheral blood mononuclear cells (PBMCs) and subjected them to DNA methylation-chip analysis (MeDIP-chip) that profiled genome-wide DNA methylation patterns on promoters of all genes and microRNAs. We next utilized the Methyl-Profiler DNA methylation assays to detect the methylation status of selected promoters. Flow cytometry and quantitative real-time PCR were used to detect the expression of the selected gene in peripheral blood cells, as well as in retinal and choroidal tissues of AMD patients and non-AMD controls. Results Our MeDIP-chip analysis identified 256 genes with hypo-methylated promoters only in the twins with AMD and 744 genes with hyper-methylated promoters only in the twins with AMD. Importantly, the promoter region of IL17RC was associated with hypo-methylated CpG sites only in the twins with AMD but not in the twins without AMD. We also found the association of the hypo-methylated IL17RC promoter with AMD in 7 pairs of siblings with discordant AMD pathology (P=0.003), as well as an independent patient cohort (95 neovascular wet and 107 geographic atrophy dry AMD patients as well as 96 non-AMD controls (95% CI, 0.01-0.10, P=9.8x10-8 for wet AMD vs. control; 95% CI, 0.05-0.32, P=2.2x10-5 for dry AMD vs. control)). Interestingly, we did not find an association between the levels of methylation on the IL17RC promoter with the previously identified genetic risk alleles in CFH, HTRA1, and ARMS2. We demonstrated an elevated expression of the IL-17RC protein in CD14+ monocytes in the peripheral blood of AMD patients as compared to non-AMD controls. These IL-17RC+ monocytes have elevated expression of CXCR1, CXCR2, and CXCR4. In addition, IL17RC was expressed only in the retinal and choroidal tissues from AMD patients but not from age-matched controls. Conclusions We show an association of the hypo-methylated IL17RC promoter with AMD, which resulted in the elevated expression of IL-17RC in peripheral blood cells as well as the retinal and choroidal tissues of AMD patients. Our study suggests that the hypo-methylated IL17RC promoter and elevated expression of IL-17RC can potentially serve as biomarkers for the diagnosis of AMD, while IL-17RC can be a new therapeutic target for AMD. In addition, our results strongly suggest an epigenetic control mechanism of AMD pathogenesis. The Affymetrix MOE430 2.0 GeneChip was used to detect gene expression patterns within the whole eye of C57B/6 normal mice.
2011-03-20 | E-GEOD-28002 | biostudies-arrayexpress
Project description:In order to find out the vital genes during retinal neovascularization (RNV), we set up OIR (oxygen-induced retinopathy; induced with 75%±2% oxygen) and wild-type C57BL/6J murine models. We observed the retinal vascular growth process daily both in OIR and wild-type mice through retinal flat-mount, and isolated total retinal RNA at different time points (P8, P9, P12, P13, P30) both in OIR and wild-type mice for gene expression analysis. At least three different retinae were accessed at each time point for observing the retinal vascular growth process. Ten neural retinae from five mice were harvested and pooled into one sample for gene expression analysis. Three biological replicates were used for each time point. Dye-swaps were performed.
2012-12-05 | E-GEOD-38762 | biostudies-arrayexpress
Project description:Age-related macular degeneration (AMD) is a leading cause of blindness in the elderly. There are two types of AMD: dry AMD and wet AMD. While laser-induced choroidal neovascularization has been used extensively in the studies of wet AMD by presenting the main features of human wet AMD, there was no established mouse model which fully recapitulates the cardinal features of human dry AMD. In this regard, lack of appropriate mouse model for dry AMD hampered the translational research on the pathogenesis and development of therapeutic agents. We recently suggested that 5XFAD mice could be a mouse model of dry AMD with regard to the amyloid beta (Aβ) related pathology. In this study, using transmission electron microscope, we analyzed ultrastructure of retinal pigment epithelium (RPE) of 5XFAD mice. Of importance, aged 5XFAD mice had ultrastructural changes of RPE and Bruchâs membrane compatible with cardinal features of dry AMD, including loss of apical microvilli and basal infolding of RPE, increased thickness of Bruchâs membrane, basal laminar and linear deposits, and accumulation of lipofuscin granules and undigested photoreceptor outer segment-laiden phagosomes. Using a threshold of 1.2 fold difference, we found â564â differentially expressed genes of which â190â were up-regulated and â374â were down-regulated in the RPE complex of aged 5XFAD mice. These altered genes were implicated in the pathogenesis of AMD including inflammation and immune response-related genes and retinol metabolism-related genes. Taken together, we suggest that aged 5XFAD mice can be used for dry AMD mouse model. All 5XFAD mice used were heterozygotes with respect to the transgene, and non-transgenic wild-type littermate (WT) mice served as controls.
2016-08-10 | E-GEOD-85408 | biostudies-arrayexpress
Project description:Background Age-related macular degeneration (AMD) is the leading cause of irreversible blindness in the elderly population worldwide. Recent studies have demonstrated strong genetic associations between AMD and single nucleotide polymorphisms (SNPs) within genes such as CFH and HTRA1. However, we have identified monozygotic twins discordant for AMD phenotypes (one with disease, the other without disease), suggesting that an epigenetic mechanism may also contribute to the pathogenesis of AMD. Methods We identified two twin pairs with phenotypic discordance of AMD. We obtained genomic DNA from their peripheral blood mononuclear cells (PBMCs) and subjected them to DNA methylation-chip analysis (MeDIP-chip) that profiled genome-wide DNA methylation patterns on promoters of all genes and microRNAs. We next utilized the Methyl-Profiler DNA methylation assays to detect the methylation status of selected promoters. Flow cytometry and quantitative real-time PCR were used to detect the expression of the selected gene in peripheral blood cells, as well as in retinal and choroidal tissues of AMD patients and non-AMD controls. Results Our MeDIP-chip analysis identified 256 genes with hypo-methylated promoters only in the twins with AMD and 744 genes with hyper-methylated promoters only in the twins with AMD. Importantly, the promoter region of IL17RC was associated with hypo-methylated CpG sites only in the twins with AMD but not in the twins without AMD. We also found the association of the hypo-methylated IL17RC promoter with AMD in 7 pairs of siblings with discordant AMD pathology (P=0.003), as well as an independent patient cohort (95 neovascular wet and 107 geographic atrophy dry AMD patients as well as 96 non-AMD controls (95% CI, 0.01-0.10, P=9.8x10-8 for wet AMD vs. control; 95% CI, 0.05-0.32, P=2.2x10-5 for dry AMD vs. control)). Interestingly, we did not find an association between the levels of methylation on the IL17RC promoter with the previously identified genetic risk alleles in CFH, HTRA1, and ARMS2. We demonstrated an elevated expression of the IL-17RC protein in CD14+ monocytes in the peripheral blood of AMD patients as compared to non-AMD controls. These IL-17RC+ monocytes have elevated expression of CXCR1, CXCR2, and CXCR4. In addition, IL17RC was expressed only in the retinal and choroidal tissues from AMD patients but not from age-matched controls. Conclusions We show an association of the hypo-methylated IL17RC promoter with AMD, which resulted in the elevated expression of IL-17RC in peripheral blood cells as well as the retinal and choroidal tissues of AMD patients. Our study suggests that the hypo-methylated IL17RC promoter and elevated expression of IL-17RC can potentially serve as biomarkers for the diagnosis of AMD, while IL-17RC can be a new therapeutic target for AMD. In addition, our results strongly suggest an epigenetic control mechanism of AMD pathogenesis.
2011-03-20 | GSE28002 | GEO