The AKT2/SIRT5/TFEB pathway as a potential therapeutic target in non-neovascular AMD
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE269923 | GEO | 2024/06/14
REPOSITORIES: GEO
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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: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: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: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:Background: Age-related macular degeneration (AMD) is caused by the degeneration of the macular photoreceptors. This is preceded by development of subretinal protein aggregates (drusen) and degeneration of the macular retinal pigment epithelium (RPE). The underlying pathogenesis remains unknown, but the immune system is suspected to play a key role in it. Aging of the immune system, immunosenescence, includes changes in T cell sub-populations and results in low-level chronic inflammation. Because AMD exclusively occurs in patients over 55 years of age, we hypothesize that aging of the T cell compartment may be implicated in AMD pathogenesis. Methodology and principal findings: Using an in vitro co-culture system, we investigated the effects of activated T cells on a human RPE cell line (ARPE-19). Differential gene expression in the RPE cells of complement factor genes was identified using microarrays, and selected gene transcripts from the alternative complement pathway were validated by q-RT-PCR. Protein expression was determined by ELISA and immunoblotting. Co-culture with activated T cells increased RPE mRNA and protein expression of complement component C3, factors B, H, H-like 1, CD46, CD59, and clusterin, in a dose-dependent manner. Conclusions: RPE cells responded to inflammatory assault caused by exposure to T cell-derived cytokines by upregulating expression of many complement factors from the alternative pathway. This may have implications for RPE ability to deal with complement attack, and opsonization and removal of debris from the RPE-choroidal interface. We speculate that regulation of the complement system in response to inflammatory assault may play a vital role in RPE pathology and drusen biogenesis. Experiment Overall Design: 10 samples investigating variations of co-cultures of RPE cells and T-cells. Variable parameters include the cell type, the co-culturing of the counter-part cell type and the orientation of the system (apical vs basolateral).
2009-10-23 | E-GEOD-17938 | biostudies-arrayexpress
Project description:Aging is the main risk factor for age-related macular degeneration (AMD), a retinal neurodegenerative syndrome that leads to irreversible blindness, particularly in people over 60 years old. Retinal pigmented epithelium (RPE) atrophy is an AMD hallmark that often precedes photoreceptor loss. Genome-wide chromatin accessibility, DNA methylation, and gene expression studies of AMD and control RPE demonstrate epigenomic/transcriptomic changes occur during AMD onset and progression. However, mechanisms by which molecular alterations of normal aging impair RPE function and contribute to AMD pathogenesis are unclear. Here, we specifically interrogate the RPE translatome with advanced age and across sexes in a novel mouse model. We find differential age- and sex- associated transcript expression with overrepresentation of pathways related to inflammation in the RPE. Concordant with impaired RPE function, the phenotypic changes in the aged translatome suggest that aged RPE becomes immunologically active, in both males and females, with some sex-specific signatures, which supports the need for sex representation for in vivo studies.
2024-05-13 | GSE245595 | GEO
Project description:We evaluate whether human induced pluripotent stem cell-derived retinal pigment epithelium (iPSC-RPE) cells can be used to prioritize and functionally characterize causal variants at age-related macular degeneration (AMD) risk loci. We generated iPSC-RPE from six subjects and show that they have morphological and molecular characteristics similar to native RPE. We generated RNA-seq, ATAC-seq, and H3K27ac ChIP-seq data and observe high similarity in gene expression and enriched transcription factor motif profiles between iPSC-RPE and human fetal-RPE. We performed fine-mapping of AMD risk loci by integrating molecular data from the iPSC-RPE, adult retina, and adult RPE, which identified rs943080 as the probable causal variant at VEGFA. We show that rs943080 is associated with altered chromatin accessibility of a distal ATAC-seq peak, decreased overall gene expression of VEGFA, and allele specific expression of a non-coding transcript. These results provide insight into the mechanism underlying the association of the VEGFA locus with AMD. Raw data requires controlled access and is deposited at dbGaP http://www.ncbi.nlm.nih.gov/gap/?term=phs000924
2019-03-30 | GSE126847 | GEO
Project description:Age-related Macular Degeneration (AMD), a blinding eye disease, is characterized by pathological protein- and lipid-rich drusen deposits underneath the retinal pigment epithelium (RPE) and atrophy of the RPE monolayer in advanced disease stages - leading to photoreceptor cell death and vision loss. Currently, there are no drugs to stop drusen formation or RPE atrophy in AMD. We developed an iPSC-RPE AMD model that recapitulates drusen and RPE atrophy. Drusen deposition is dependent on AMD-risk-allele CFH(H/H) and anaphylatoxin triggered alternate complement signaling via the activation of NF-B and downregulation of autophagy pathways. High-throughput screen identified two drugs, L-745,870, a dopamine receptor antagonist, and aminocaproic acid, a protease inhibitor that reduce drusen deposits and restore RPE epithelial phenotype in anaphylatoxin challenged iPSC-RPE with or without the CFH(H/H) genotype. This comprehensive iPSC-RPE model replicates key AMD phenotypes, provides molecular insight into the role of CFH(H/H) risk-allele in AMD, and discovers two candidate drugs to treat AMD.
2021-10-12 | GSE185310 | 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: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