Microglia-RPE Cell Communication via the SPP1-ITGAV Axis Drives EMT and Retinal Degeneration in Dry AMD
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ABSTRACT:
PROVIDER: PRJNA1183307 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR31266546_1.fastq.gz | Fastqsanger.gz | |||
| SRR31266546_2.fastq.gz | Fastqsanger.gz | |||
| SRR31266549_1.fastq.gz | Fastqsanger.gz | |||
| SRR31266549_2.fastq.gz | Fastqsanger.gz | |||
| SRR31266552_1.fastq.gz | Fastqsanger.gz |
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Project description:Age-related macular degeneration (AMD) is a leading cause of vision loss, with its dry form characterized by retinal pigment epithelium (RPE) degeneration and photoreceptor loss. However, the underlying mechanisms driving these pathological changes remain poorly understood. Here, we identify a critical role for microglia-RPE cell interactions mediated by the SPP1-ITGAV signaling axis in dry AMD pathogenesis.
2024-11-12 | GSE281280 | GEO
Project description:Comparing fibroblasts and derived -iPSC and - RPE cells from human AMD and non-AMD donors Retinal pigment epithelium (RPE) generated from skin biopsies of donors with age-related macular degeneration (AMD) exhibit a disease phenotype and a distinct transcriptome compared to age-matched controls. We investigated whether similar differences existed in the skin fibroblasts and induced pluripotent stem cells (iPSCs) derived from them. Hierarchical cluster and principal component analyses revealed significant overlap in the transcriptome of fibroblasts of AMD and non-AMD donors. After reprogramming, iPSCs exhibited slight differences. In contrast, the transcriptome of RPE derived from AMD and normal donors segregated into two distinct clusters. Differences in the expression of specific genes that were evident between normal and AMD-derived RPE were not observed in fibroblasts or iPSCs. Mitochondrial respiration was reduced in RPE from AMD patients but not in fibroblast or iPSCs. RPE derived from AMD patients have a distinct transcriptome and phenotype compared to controls that is not observed in their corresponding skin fibroblasts or iPSCs.
2024-04-23 | GSE149202 | GEO
Project description:Comparing iPS derived RPE cells from human AMD and non-AMD donors It has been a challenge to model retinal disorders such as geographic atrophy (GA) in in vivo animals, primarily because several factors, including genetics and aging itself, contribute to disease phenotype of age-related macular degeneration (AMD). We generated retinal pigment epithelial (RPE) cells from patients with advanced AMD and assessed their ability to model disease. We observed alterations in the transcriptome of AMD patients compared to non-diseased controls. RPE cells from AMD patients displayed decreases in mitochondrial function (basal respiration and adenosine triphosphate (ATP) production) compared with non-diseased controls. Using a system of mimicing AMD diseased ECM, we showed RPE cells derived from patients with AMD have a reduced ability to survive and proliferate on nitrite-modified extracellular matrix (ECM) when compared to non-diseased controls. These results demonstrate changes in the cell biology and phenotype of RPE cells from patients with advanced AMD, providing a platform for disease modeling to understand AMD pathophysiology.
2020-02-26 | GSE125564 | GEO
Project description:iPSC-RPE cells derived from a patient with AMD, whom harboured the Y402H mutation were compared to healthy donor RPE cells.
2017-12-19 | GSE91087 | 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 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: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 the leading cause of blindness in seniors, with no effective treatment options available for most patients. AMD is characterized by the death of retinal pigment epithelium (RPE) and photoreceptors, resulting in central vision loss causing tremendous difficulties in performing daily tasks requiring visualization of fine details visualization. Dysfunction of RPE mitochondria is a critical early event involved in AMD pathogenesis, and we previously reported that maintaining normal mitochondrial functions in RPE could be a viable option for AMD treatment. We hypothesize that dysregulation of RPE mitochondrial proteome is highly relevant to the loss of RPE mitochondrial function during the transition from healthy aging to early AMD. The hypothesis was examined by quantitative proteomics using UHR-IonStar.
2022-07-13 | PXD033413 | Pride
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:How retinal pigmented epithelial (RPE) cells degenerate from oxidative stress in age-related macular degeneration (AMD) is incompletely understood. The study's intent was to identify key cytoprotective pathways activated by oxidative stress, and to determine the extent of their protection. Immunohistochemistry was used to identify the unfolded protein response (UPR) and mitochondria in the RPE of AMD samples. Maculas with early AMD had prominent IRE1α, but minimal mitochondrial TOM20 immunolabeling in mildly degenerated RPE. RPE cells treated with cigarette smoke extract (CSE), by microarray analysis, had over-represented genes involved in the antioxidant and unfolded protein response, and mitochondrial location. CSE induced the UPR sensors IRE1α, p-PERK, and ATP6, which activated CHOP. CHOP knockdown compromised cell viability after CSE exposure. At the same CSE doses, mitochondria generated superoxide anion and produced less ATP. In mice given intravitreal CSE, the RPE had increased IRE1α and decreased ATP, which elicited RPE epithelial-mesenchymal transition, as suggested by altered ZO1 immunolabeling of RPE flatmounts. Our experiments indicate that RPE cells exposed to oxidative stress respond with a cytoprotective antioxidant and unfolded protein response, but develop mitochondrial impairment that contributed to epithelial mesenchymal transition. With similar responses in the RPE of early AMD samples, these results suggest that mitochondria are vulnerable to oxidative stress while the ER elicits a protective response during early AMD. A total of 9 samples were analyzed: 3 control samples, 3 samples treated with 100ug/ml of Cigarette Smoke Condensate, and 3 samples treated with 250ug/ml of Cigarettes Smoke Condensate.
2014-01-30 | E-GEOD-49107 | biostudies-arrayexpress
Project description:Non-neovascular or dry age-related macular degeneration (AMD) is a multi-factorial disease with degeneration of the aging retinal-pigmented epithelium (RPE) as a central pathogenic driver. Lysosomes play a crucial role in RPE health due to their involvement in phagocytosis and autophagy, which are regulated by transcription factor EB/E3 (TFEB/E3). Disruption in these processes can accelerate aging disorders, like AMD. Here we tried to ascertain if upregulation of AKT2 in the RPE cells triggers abnormalities lysosomal/autophagy processes and mitochondrial function culminating into an early AMD-like phenotype using mouse and in vitro "disease in a dish" models as tools.
2024-06-14 | GSE269923 | GEO