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A systems biology approach uncovers novel disease mechanisms in age-related macular degeneration [mouse_retina_scRNAseq]

ABSTRACT: We investigated the cell type composition of mouse retinas and identified which cell type(s) express genes we identified as being AMD-associated in human patients. We generated Dram2 KO mice to investigate how DRAM2 loss affects the mouse retina. Our in vitro data showed that DRAM2 loss affects human stem cell-derived eye organoids, we investigate if it is the case in mice.

ORGANISM(S): Mus musculus

PROVIDER: GSE220626 | GEO | 2023/09/15

REPOSITORIES: GEO

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A systems biology approach uncovers novel disease mechanisms in age-related macular degeneration [human_retinal_organoid]

Project description:We have optimized CRISPR/Cas genome editing in human Embryonic Stem Cells (hESCs) and developed a method to generate hESC-derived eye organoids to investigate the cell type composition of these eye organoids using single cell RNA sequencing. We also investigate the consequences of the loss of a new AMD-associated gene, DRAM2, on the cell composition of the eye organoids.

2023-09-15 | GSE220624 | GEO

A systems biology approach uncovers novel disease mechanisms in age-related macular degeneration [mouse_choroid_scRNAseq]

Project description:We are investigating the AMD-associated gene DRAM2. Our in vitro data showed that DRAM2 loss in human embryonic stem cell derived eye organoids generates a distinct fibroblast-like population secreting proteins related to connective tissue extracellular matrix. We generated Dram2 KO mice and did scRNA-seq on cells from the retina, and did not find any significant difference between DRAM2 KO and WT. However, our data from human organoids indicates that the difference should be in the choroid, and not in the retina of the eye. Indeed, we find that DRAM2 KO cells from mouse choroid have a growth advantage compared with WT. Here we investigate the cell type composition of mouse choroid and identify putative genes responsible for the growth advantage in DRAM2 KO choroid cells.

2023-09-15 | GSE220625 | GEO

Therapeutic effects of Tie2 activation in treatment of neovascular age-related macular degeneration over conventional VEGF blockade.

Project description:To investigate a potential therapeutic effect of ABTAA on NV-AMD, we employed a mouse model of laser-induced CNV, that mimics human NV-AMD. A laser photocoagulation on mouse retinas was performed to rupture RPE and Bruch’s membrane, and then the effects of ABTAA were compared with those of VEGF-Trap.

2018-10-01 | GSE88730 | GEO

A systems biology approach uncovers novel disease mechanisms in age-related macular degeneration.

Project description:This SuperSeries is composed of the SubSeries listed below.

2023-09-15 | GSE220627 | GEO

Systems-level analysis of age-related macular degeneration reveals global and subtype-specific functional pathways

Project description:Age-related macular degeneration (AMD) is a leading cause of human blindness in developed countries. While significant inroads have been made over the past decade, an integrated description of the molecular mechanisms underlying AMD has yet to emerge. Here we describe a systems-level transcriptome analysis of the retina and retinal pigmented epithelium (RPE)-choroid complex from 31 normal, 26 AMD, and 11 potential pre-AMD human eyes derived from the University of Iowa. Our analysis identifies cell-mediated immune responses as the central feature of dry AMD, wet AMD, and geographic atrophy (GA), and we confirm this finding using a second cohort of donor eyes obtained from the Lion's Eye Bank of Oregon. In addition, in the RPE-choroid, we identify the major up-regulated pathways in GA and wet AMD as apoptosis and angiogenesis, respectively. In the retina, a graded up-regulation of wound response, complement, and neurogenesis pathway genes strongly correlates with advanced stages of AMD, in parallel with a progressive down-regulation of key phototransduction processes. Finally, using expression signatures enriched in functional pathways, we assemble two detailed AMD interactomes that highlight modular gene expression programs that delineate and interconnect dry, wet, and GA AMD subtypes across both RPE-choroid and retina tissues. In total, these interactomes are comprised of over 150 genes of which 23 have been previously associated with AMD. These data provide new insights into the expression landscape of AMD pathophysiology, and reveal numerous new targets for AMD pharmaceuticals and diagnostics.

2012-02-14 | GSE29801 | GEO

Autophagy in age-related macular degeneration using Vldlr KO mouse model of retinopathy

Project description:Autophagy plays vital housekeeping neuronal functions but is not believed to fuel energy metabolism. Autophagy regulation by lipids nutrient sensors have not been identified. Cone photoreceptors’ very-low-density lipoprotein receptor (Vldlr) expression facilitates the uptake of triglyceride-derived fatty acid. In Vldlr-/- mice, we identify free fatty acid receptor 1 (Ffar1) as a suppressor of transcription factor EB (Tfeb), a master regulator of autophagy. Tfeb, in turn, governs the expression of PGC1 and Sirtuin-3, leading to reduced -ketoglutarate (-KG). We recently showed that low -KG in Vldlr-/- photoreceptors drives Vegfa expression and neovascularization reminiscent of a subset of age-related macular degeneration (AMD). Metabolomics of human AMD vitreous and Vldlr-/- retinas identified a similar Krebs cycle metabolite signature. Improving autophagy in AMD-like mice rescued the neovascular phenotype and vision. Dysregulated autophagy may therefore compound the energy failure of photoreceptors contributing to neovascular AMD and could be a driving force in other neovascular diseases.

2022-02-24 | GSE110623 | GEO

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 (AÎ²) 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

Epigenetic Regulation of IL17RC in Age-related Macular Degeneration (MeDIP-chip)

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

Large-Scale Quantitative Proteomics of Retinal Mitochondrial Fractions from Age-Related Macular Degeneration (AMD) Patients

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

Epithelial phenotype restoring drugs suppress macular 1 degeneration phenotypes in an iPSC model

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

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