Stress resilience-enhancing drugs preserve tissue structure and function in degenerating retina via selective phosphodiesterase inhibition
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE208760 | GEO | 2023/05/01
REPOSITORIES: GEO
Similar Datasets
Project description:Chronic, progressive retinal diseases, such as age-related macular degeneration (AMD), diabetic retinopathy, and retinitis pigmentosa, arise from genetic and environmental perturbations of cellular and tissue homeostasis. These disruptions accumulate with repeated exposures to stress over time, leading to progressive visual impairment and, in many cases, legal blindness. Despite decades of research, therapeutic options for the millions of patients suffering from these disorders remain severely limited, especially for treating earlier stages of pathogenesis when the opportunity to preserve the retinal structure and visual function is greatest. To address this urgent, unmet medical need, we employed a systems pharmacology platform for therapeutic development. Through integrative single-cell transcriptomics, proteomics, and phosphoproteomics, we identified universal molecular mechanisms across distinct models of age-related and inherited retinal degenerations, characterized by impaired physiological resilience to stress. Here, we report that selective, targeted pharmacological inhibition of cyclic nucleotide phosphodiesterases (PDEs), which serve as critical regulatory nodes that modulate intracellular second messenger signaling pathways, stabilized the transcriptome, proteome, and phosphoproteome through downstream activation of protective mechanisms coupled with synergistic inhibition of degenerative processes. This therapeutic intervention enhanced resilience to acute and chronic forms of stress in the degenerating retina, thus preserving tissue structure and function across various models of age-related and inherited retinal disease. Taken together, these findings exemplify a systems pharmacology approach to drug discovery and development, revealing a new class of therapeutics with potential clinical utility in the treatment or prevention of the most common causes of blindness.
| S-EPMC10175720 | biostudies-literature
Project description:Stress resilience-enhancing drugs preserve tissue structure and function in degenerating retina via selective phosphodiesterase inhibition
| PRJNA860959 | ENA
Project description:To determine the gene expression changes in the retina of miR-204/miR-211 RPE conditional knockout (dKO) mice, we collected retina samples from dKO and controls animals at 6 months of degeneration, generated single-cell suspensions, and created scRNA-seq libraries (Parse Biosciences), and sequened the libraries.
2024-06-05 | GSE255851 | GEO
Project description:Vision depends on the functional interplay between the photoreceptor cells of the neural retina and the supporting cells of the underlying retinal pigment epithelium (RPE). Many genes involved in inherited retinal diseases (IRD) display highly specific spatiotemporal expression within these interconnected retinal components through the local recruitment of cis-regulatory elements (CREs) in 3D nuclear space. To understand the role of differential chromatin architecture in establishing tissue-specific expression patterns at IRD loci in the human neural retina and the RPE, we mapped genome-wide chromatin interactions by applying in situ Hi-C and H3K4me3 HiChIP to human adult post-mortem donor retinas. A comparative 3D genome analysis between neural retina and RPE revealed that almost 60% of known IRD genes were marked by differential cis-regulatory interactions or 3D genome structure. Furthermore, we zoomed in on tissue-specific chromatin interactions at the ABCA4 locus, which is implicated in the most common autosomal recessive IRD. We constructed high-resolution ABCA4 interaction profiles using UMI-4C, which, upon integration with bulk and single-cell epigenomic datasets and in vivo enhancer assays in zebrafish, revealed tissue-specific CREs for ABCA4. In summary, through extensive comparative 3D genome mapping, based on genome-wide (Hi-C), promoter-centric (HiChIP) and locus-specific (UMI-4C) assays of human neural retina and RPE, we have shown that gene regulation at key IRD loci is likely mediated by tissue-specific chromatin interactions. These findings do not only provide insight into tissue-specific regulatory landscapes at retinal disease loci, but also delineate the search space for genomic variation underlying unsolved IRD.
2024-04-08 | GSE236021 | GEO
Project description:Vision depends on the functional interplay between the photoreceptor cells of the neural retina and the supporting cells of the underlying retinal pigment epithelium (RPE). Many genes involved in inherited retinal diseases (IRD) display highly specific spatiotemporal expression within these interconnected retinal components through the local recruitment of cis-regulatory elements (CREs) in 3D nuclear space. To understand the role of differential chromatin architecture in establishing tissue-specific expression patterns at IRD loci in the human neural retina and the RPE, we mapped genome-wide chromatin interactions by applying in situ Hi-C and H3K4me3 HiChIP to human adult post-mortem donor retinas. A comparative 3D genome analysis between neural retina and RPE revealed that almost 60% of known IRD genes were marked by differential cis-regulatory interactions or 3D genome structure. Furthermore, we zoomed in on tissue-specific chromatin interactions at the ABCA4 locus, which is implicated in the most common autosomal recessive IRD. We constructed high-resolution ABCA4 interaction profiles using UMI-4C, which, upon integration with bulk and single-cell epigenomic datasets and in vivo enhancer assays in zebrafish, revealed tissue-specific CREs for ABCA4. In summary, through extensive comparative 3D genome mapping, based on genome-wide (Hi-C), promoter-centric (HiChIP) and locus-specific (UMI-4C) assays of human neural retina and RPE, we have shown that gene regulation at key IRD loci is likely mediated by tissue-specific chromatin interactions. These findings do not only provide insight into tissue-specific regulatory landscapes at retinal disease loci, but also delineate the search space for genomic variation underlying unsolved IRD.
2024-04-08 | GSE235728 | GEO
Project description:Vision depends on the functional interplay between the photoreceptor cells of the neural retina and the supporting cells of the underlying retinal pigment epithelium (RPE). Many genes involved in inherited retinal diseases (IRD) display highly specific spatiotemporal expression within these interconnected retinal components through the local recruitment of cis-regulatory elements (CREs) in 3D nuclear space. To understand the role of differential chromatin architecture in establishing tissue-specific expression patterns at IRD loci in the human neural retina and the RPE, we mapped genome-wide chromatin interactions by applying in situ Hi-C and H3K4me3 HiChIP to human adult post-mortem donor retinas. A comparative 3D genome analysis between neural retina and RPE revealed that almost 60% of known IRD genes were marked by differential cis-regulatory interactions or 3D genome structure. Furthermore, we zoomed in on tissue-specific chromatin interactions at the ABCA4 locus, which is implicated in the most common autosomal recessive IRD. We constructed high-resolution ABCA4 interaction profiles using UMI-4C, which, upon integration with bulk and single-cell epigenomic datasets and in vivo enhancer assays in zebrafish, revealed tissue-specific CREs for ABCA4. In summary, through extensive comparative 3D genome mapping, based on genome-wide (Hi-C), promoter-centric (HiChIP) and locus-specific (UMI-4C) assays of human neural retina and RPE, we have shown that gene regulation at key IRD loci is likely mediated by tissue-specific chromatin interactions. These findings do not only provide insight into tissue-specific regulatory landscapes at retinal disease loci, but also delineate the search space for genomic variation underlying unsolved IRD.
2024-04-08 | GSE235726 | GEO
Project description:ST2 heterodimerizes with IL-1RAcp to form the receptor for IL-33, which is primarily associated with allergic inflammation by inducing Th2 responses. Recently, however, IL-33 was found to be expressed in the central nervous system and in retinal Muller cells which imply functions, as yet undescribed, beyond Th2 mediated inflammation. Muller cells support the health of the retina and photoreceptors and are also involved in inflammation in retinal degeneration. It is not known how IL-33/ST2 functions in this capacity. We recently found that ST2 ko mice are protected from CLE-induced photoreceptor loss, implying a detrimental effect of IL33/ST2 in CLE. We wish to perform microarray analysis using WT and ST2 KO mice in CLE model to better understand the mechanism by which IL-33/ST2 regulates retinal degeneration. CLE (Constant Light Exposure) is a model of retinal damage/degeneration in mice. Mice are exposed to bright light 24 hours a day for a period of time which damages retina photoreceptors. This damage is assessed by histology, optical coherence tomography (OCT), which measures retina thickness in vivo. In this experiment, the WT and ST2 KO mice (5 mice per genotype per time point) will be exposed to 1200-lux constant light for 0, 3, 10 days. The retinal RNA will be isolated and analyzed for differential gene expression by microarray.
2015-12-17 | E-GEOD-74695 | biostudies-arrayexpress
Project description:We report RNA-Seq analysis of the transcriptome of retinas and RPE/choroids from Abca4 knockout, Abca4 L541P;A1038V knockin and control wild type mice in order to better understand changes in gene regulation that could lead to retinal pathology in mice with ABCA4 deficiency/defect. Retinal and RPE/choroidal mRNA profiles of 30-day-old wild type (WT), Abca4-/- and Abca4L541P;A1038V/L541P;A1038V mice were generated by RNA-Seq, using Illumina Hiseq 2500
2015-04-07 | E-GEOD-63772 | biostudies-arrayexpress
Project description:We wanted to transcriptomically compare single cells taken from the retinas of C57BL6/J mice, Abca4-/-Rdh8-/- (dKO) mutant mice, and Abca4PV/PVRdh8-/- (PVR) mutant mice before and at an early (24-hour post-bleach) timepoint post-bleaching, to see if the two Abca4 mutants displayed different transcriptomic shifts in response to intense light, which initiates retinal degeneration. Additionally, we wanted to determine if the two mutants had different transcriptional responses to the immunomodulatory drug maraviroc. The wild-type C57BL6/J mice were included as controls for each treatment condition. We profiled the three cohorts of mice under three separate treatment conditions: without light-induced degeneration, 24-hours post-bleaching with intense light and vehicle treatment, and 24-hours post-bleaching with intense light and maraviroc treatment. Single cell isolates were collected, fixed, barcoded, and sequenced using kits from Parse Biosciences.
2023-11-16 | GSE239347 | GEO
Project description:Endogenous glucocorticoids (GCs) are pivotal in controlling inflammation. Keratinocyte-derived GCs contribute to local skin homeostasis as deletion of the GC-producing enzyme 11β-hydroxylase (Cyp11b1) in keratinocytes exacerbated skin inflammation. Since local tamoxifen-induced knockout (KO) induction may contribute to skin irritation, we implemented intraperitoneal injections to induce a systemic skin GC depletion preventing experimental skin irritation in order to reveal the importance of skin GC in steady-state. Both, local and systemic skin GC deficiency models exhibited reduced skin GC levels and increased migration of skin antigen-presenting cells to draining lymph nodes. However, systemic skin GC ablation did not result in pronounced skin inflammation as seen in local model. Interestingly, systemic skin GC deficiency elevated systemic inflammatory markers and provoked adrenal GC synthesis. RNA sequencing of keratinocytes revealed distinct gene expression patterns between local and systemic KOs. Local skin GC ablation showed a stronger inflammatory and apoptotic response, while systemic skin GC deficiency triggered several compensatory regulatory pathways, mitigating extensive skin inflammation. These findings underscore the critical role of local GCs in skin immune resilience against minor skin irritations and highlight the interplay between skin and adrenal GC levels.
2024-08-01 | GSE271160 | GEO