ALKBH5 induces retinal pigment epithelium anomalies and choroidal neovascularization in age-related macular degeneration via PIK3C2B/AKT/mTOR pathway
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE212914 | GEO | 2022/09/12
REPOSITORIES: GEO
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Project description:ALKBH5 induces retinal pigment epithelium anomalies and choroidal neovascularization in age-related macular degeneration via PIK3C2B/AKT/mTOR pathway
| PRJNA878456 | ENA
Project description:Purpose: Age-related degeneration (AMD) is a major cause of blindness in developed countries. The molecular pathogenesis of early events in AMD is poorly understood. We investigated differential gene expression in samples of human retinal pigment epithelium (RPE)/choroid from early AMD and control maculas using exon-based arrays. Methods: Gene expression levels in nine early AMD and nine control human donor eyes were assessed using Affymetrix Human Exon ST 1.0 arrays. Two controls did not pass quality control and were removed. Differentially expressed genes were annotated using DAVID, and gene set enrichment analysis (GSEA) was performed on RPE-specific and endothelium-associated gene sets. CFH genotype was also assessed and differential expression was analyzed with respect to high AMD risk (YH/HH) and low AMD risk (YY) genotypes. Results: Seventy-five genes were identified as differentially expressed (raw p-value < 0.01; >50% fold change, mean log2 expression level in AMD or control M-bM-^IM-% median of all average gene expression values); however, no genes were significant (adj. p-value < 0.01) after correction for multiple hypothesis testing. Of 52 genes with decreased expression in AMD (fold change < 0.5; raw p-value < 0.01), 18 genes were identified by DAVID analysis as associated with vision or neurological processes. GSEA of RPE-associated and endothelium-associated genes revealed a significant decrease in genes typically expressed by endothelial cells in the early AMD group compared to controls, consistent with previous histologic and proteomic studies. Analysis with respect to CFH genotype indicated decreased expression of ADAMTS9 in eyes with high-risk genotypes (fold change = -2.61; raw p-value = 0.0008). Conclusions: GSEA results suggest that RPE transcripts are preserved or elevated in early AMD, concomitant with loss of endothelial cell marker expression. These results are consistent with the notion that choroidal endothelial cell dropout occurs early in the pathogenesis of AMD. Using AltAnalyze (ver. 2.0.7 beta), we analyzed nine early AMD and nine control eyes using Affymetrix Human Exon ST 1.0 arrays. Following initial processing in AltAnalyze, two control arrays were identified as potential outliers by tests implement in arrayQualityMetrics, a package for R.
2013-12-23 | E-GEOD-50195 | biostudies-arrayexpress
Project description:PurposeTo use optical coherence tomography angiography (OCTA) to study longitudinal subclinical choroidal neovascularization (CNV) changes and their correlation with progression to exudation in age-related macular degeneration (AMD).MethodsThis study included a total of 34 patients with unilateral neovascular AMD who were evaluated prospectively using OCTA to detect subclinical CNV in their fellow eye. Eyes with baseline subclinical CNV were followed with serial OCTA for a minimum of one year (15.2±3.27 months) to monitor the development of exudation.ResultsOf the 34 fellow eyes studied, five were found to have baseline subclinical CNV. One of the five cases of baseline subclinical CNV converted to exudative AMD during the follow up period. The average surface area of baseline subclinical CNV on OCTA was 0.131±0.096 mm2 which progressed to 0.136±0.104 mm2 at the final follow up (P = 0.539). Geographic atrophy grew at a rate of 0.82±1.20mm2/year in four eyes without subclinical CNV and 0.02mm2/year in one eye with subclinical CNV.Conclusion and importanceThe rate of conversion to exudative AMD in eyes with subclinical CNV of 20% in our study is similar to previous reports and suggests the importance of vigilance in these eyes. The lower growth rate of geographic atrophy may suggest a protective effect of subclinical CNV that deserves further study.
| S-EPMC6548359 | biostudies-literature
Project description:Visual outcome of patients with neovascular age-related macular degeneration has significantly improved during the last years as a result of anti-VEGF therapy. However, some patients show persistent exudation and decreasing visual acuity despite recurrent anti-VEGF injections, indicating a role of other proangiogenic mediators. The present study applied transcriptional profiling of human and mouse CNV membranes each with reference to healthy control tissue to identify novel mediators of CNV. Following this approach, the study identifies Fibroblast growth factor induci-ble-14 (FN14) as a novel phylogenetically conserved mediator of CNV. Blocking the pathway by intravitreal injection of an FN14 decoy receptor modulates the cytokine profile - most notably IL-6 - and leads to a significant and IL-6 mediated reduction of CNV size in vivo. These results identify FN14 as a promising new therapeutic target for neovascular AMD, which may potentially be beneficial in patients with exudative AMD with special regard to anti-VEGF resistant cases.
2022-06-30 | GSE163090 | GEO
Project description:Purpose: Age-related degeneration (AMD) is a major cause of blindness in developed countries. The molecular pathogenesis of early events in AMD is poorly understood. We investigated differential gene expression in samples of human retinal pigment epithelium (RPE)/choroid from early AMD and control maculas using exon-based arrays. Methods: Gene expression levels in nine early AMD and nine control human donor eyes were assessed using Affymetrix Human Exon ST 1.0 arrays. Two controls did not pass quality control and were removed. Differentially expressed genes were annotated using DAVID, and gene set enrichment analysis (GSEA) was performed on RPE-specific and endothelium-associated gene sets. CFH genotype was also assessed and differential expression was analyzed with respect to high AMD risk (YH/HH) and low AMD risk (YY) genotypes. Results: Seventy-five genes were identified as differentially expressed (raw p-value < 0.01; >50% fold change, mean log2 expression level in AMD or control ≥ median of all average gene expression values); however, no genes were significant (adj. p-value < 0.01) after correction for multiple hypothesis testing. Of 52 genes with decreased expression in AMD (fold change < 0.5; raw p-value < 0.01), 18 genes were identified by DAVID analysis as associated with vision or neurological processes. GSEA of RPE-associated and endothelium-associated genes revealed a significant decrease in genes typically expressed by endothelial cells in the early AMD group compared to controls, consistent with previous histologic and proteomic studies. Analysis with respect to CFH genotype indicated decreased expression of ADAMTS9 in eyes with high-risk genotypes (fold change = -2.61; raw p-value = 0.0008). Conclusions: GSEA results suggest that RPE transcripts are preserved or elevated in early AMD, concomitant with loss of endothelial cell marker expression. These results are consistent with the notion that choroidal endothelial cell dropout occurs early in the pathogenesis of AMD.
2013-12-23 | GSE50195 | GEO
Project description:Age related macular degeneration (AMD) is a leading cause of legal blindness. Vision loss is caused by the retinal pigment epithelium (RPE) and photoreceptors loss and/or retinal and choroidal angiogenesis. Here we report enhanced polarised secretion of extracellular vesicles (EVs) in complement factor H (CFH) Y402H AMD patient specific RPE. As indicated by multi ‘omics analyses, AMD RPE EVs carry a repertoire of RNA, proteins and lipids that reflect disease changes in the RPE cells of origin and mediate pathological processes such as oxidative stress, cytoskeletal dysfunction and angiogenesis. We demonstrate that exposure of control RPE to AMD RPE EVs leads to the formation of numerous cytoplasmic stress vacuoles, cytoskeletal destabilization, and abnormalities in the morphology of the nucleus in the recipient cells. Treatment of laminated retinal organoids containing photoreceptor cells with apical AMD RPE EVs leads to disrupted neuroepithelium and appearance of enlarged cells immunopositive for cytoprotective alpha B crystallin. The presence of cells expressing alpha B crystallin and progenitor cells markers Pax6 or Vsx2 are consistent with the activation of regenerative pathways upon injury. These findings suggest that AMD RPE EVs act as signalling messengers in the outer retina and may be involved in disease progression.
2022-12-28 | GSE190263 | GEO
Project description: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 found monozygotic twins had discordant AMD phenotypes (one with disease, the other without disease), suggesting that an epigenetic mechanism may control the pathogenesis of AMD. We obtained genomic DNA from the twins' peripheral blood mononuclear cells (PBMCs) and subjected it to DNA methylation-chip analysis (MeDIP-chip) that profiled genome-wide DNA methylation patterns on promoters of all genes and microRNAs. 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. Two pairs of twins with discordant AMD phenotypes. MeDIP-chip analysis of DNA methylation patterns in PBMCs.
2011-03-21 | E-GEOD-28032 | biostudies-arrayexpress
Project description:PurposeTo detect and quantify choroidal neovascularization (CNV) in patients with age-related macular degeneration (AMD) using optical coherence tomography (OCT) angiography.DesignObservational, cross-sectional study.ParticipantsA total of 5 normal subjects and 5 subjects with neovascular AMD were included.MethodsA total of 5 eyes with neovascular AMD and 5 normal age-matched controls were scanned by a high-speed (100 000 A-scans/seconds) 1050-nm wavelength swept-source OCT. The macular angiography scan covered a 3 × 3-mm area and comprised 200 × 200 × 8 A-scans acquired in 3.5 seconds. Flow was detected using the split-spectrum amplitude-decorrelation angiography (SSADA) algorithm. Motion artifacts were removed by 3-dimensional (3D) orthogonal registration and merging of 4 scans. The 3D angiography was segmented into 3 layers: inner retina (to show retinal vasculature), outer retina (to identify CNV), and choroid. En face maximum projection was used to obtain 2-dimensional angiograms from the 3 layers. The CNV area and flow index were computed from the en face OCT angiogram of the outer retinal layer. Flow (decorrelation) and structural data were combined in composite color angiograms for both en face and cross-sectional views.Main outcome measuresThe CNV angiogram, CNV area, and CNV flow index.ResultsEn face OCT angiograms of CNV showed sizes and locations that were confirmed by fluorescein angiography (FA). Optical coherence tomography angiography provided more distinct vascular network patterns that were less obscured by subretinal hemorrhage. The en face angiograms also showed areas of reduced choroidal flow adjacent to the CNV in all cases and significantly reduced retinal flow in 1 case. Cross-sectional angiograms were used to visualize CNV location relative to the retinal pigment epithelium and Bruch's layer and classify type I and type II CNV. A feeder vessel could be identified in 1 case. Higher flow indexes were associated with larger CNV and type II CNV.ConclusionsOptical coherence tomography angiography provides depth-resolved information and detailed images of CNV in neovascular AMD. Quantitative information regarding CNV flow and area can be obtained. Further studies are needed to assess the role of quantitative OCT angiography in the evaluation and treatment of neovascular AMD.
| S-EPMC4082740 | biostudies-literature
Project description:Purpose: The goals of this study were to identify expression patterns in a large population of human donor choroids, including donors with early atrophic AMD Methods: Independent libraries were prepared for choroidal cells from twenty human donors. Macular samples from donors 1,2,3,5, 11, and 12 were acquired, analyzed, and uploaded in previous experiments (GSE135922 - donors 1,2, 11, and 12; GSE149100- donors 3 and 5). Choroidal punches were gently dissociated in collagenase II for 1 hour before cryopreservation. Thawed cells underwent endothelial cell enrichment by incubating with anti-CD31-microbeads. Final libraries were sequenced on an Illumina NovaSeq system. Sequenced reads were mapped to the human genome build hg38 with CellRanger(v6.0.0) and filtered to remove cells likely to be doublets or cells with a high proportion of mitochondrial reads. Feature selection was performed with the variance stabilizing transformation before integration was performed with Seurat (v4). Results: A total of 30416 cells were recovered after filtering with 5,607,479,828 corresponding reads. A total of 17097 cells were recovered from AMD donor libraries while 13319 cells were recovered from control donors. Clusters were assigned to known choroidal cell types based on expression of distinguishing marker genes. Differential expression analysis identified genes enriched in each population of cells originating from AMD versus control libraries. Particular emphasis was given to choriocapillaris endothelial cells. Conclusions: This study characterizes new gene expression signatures for several choroidal cells, including tissue resident macrophages, inflammatory macrophages, arterioles, and venules.
2022-02-21 | GSE183320 | GEO
Project description:Age-related macular degeneration (AMD) is a leading cause of blindness. Vision loss is caused by the loss of the retinal pigment epithelium (RPE) and photoreceptors and/or retinal and choroidal angiogenesis. Here we use AMD patient specific RPE cells with the Y402H high-risk polymorphism in the complement factor H to perform a comprehensive analysis of EVs, their cargo and role in disease pathology. We show that AMD RPE is characterised by enhanced and polarised EV secretion. Transcriptomic, proteomic and lipidomic analyses demonstrate that AMD RPE EVs carry RNA, proteins and lipids that reflect changes in the parental RPE and mediate key AMD pathological processes including oxidative stress, cytoskeletal dysfunction, angiogenesis and drusen accumulation. We demonstrate that exposure of control RPE to AMD RPE apical EVs leads to the formation of stress vacuoles, cytoskeletal destabilization, and abnormalities in the morphology of the nucleus in the recipient cells. Treatment of retinal organoids with apical AMD RPE EVs leads to disrupted neuroepithelium and appearance of cytoprotective alpha B crystallin immunopositive cells, with some co-expressing retinal progenitor cell markers Pax6 or Vsx2, suggesting activation of regenerative pathways upon injury. These findings indicate that AMD RPE EVs mediated signalling have an important role in disease progression.
2022-01-21 | MSV000088713 | MassIVE