An in vitro high-content screening unveils miR-429 as a protective molecule in photoreceptor degeneration models
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ABSTRACT:
PROVIDER: PRJNA1137943 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR29892960_1.fastq.gz | Fastqsanger.gz | |||
| SRR29892960_2.fastq.gz | Fastqsanger.gz | |||
| SRR29892961_1.fastq.gz | Fastqsanger.gz | |||
| SRR29892961_2.fastq.gz | Fastqsanger.gz | |||
| SRR29892962_1.fastq.gz | Fastqsanger.gz |
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Project description:Transcriptome profile of optic cups from RhoP23H/+ mice following AAV-mediated subretinal delivery of pre-miR-429 or GFP (control vector) to study the molecular changes underlying the neuroprotective effect of miR-429 overexpression in an Inherited Retinal Disease (IRD) model.
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Project description:To investigate pathogenic mechanisms in such instances, we have characterized rod photoreceptor and retinal gene expression changes in response to a defined insult to photoreceptor structure, using the retinal degeneration slow (rds) mouse model. Global gene expression profiling was performed on flow-sorted rds and wild-type rod photoreceptors immediately prior and subsequent to times at which OSs are normally elaborated. Dysregulated genes were identified via microarray hybridization, and selected candidates were validated using quantitative PCR analyses. We identified a single key gene, Egr1, that was dysregulated in a sustained fashion in rds rod photoreceptors and in the retina. Egr1 upregulation was associated with microglial activation and migration, into the outer retina at times subsequent to the major peak of photoreceptor cell death. Interestingly, this response was accompanied by neurotrophic factor upregulation. We hypothesize that activation of Egr1 and neurotrophic factors represents a protective immune mechanism, contributing to the characteristically slow retinal degeneration of the rds mouse model. We had two conditions WT and Rds-KO at 4 different time points: postnatal (P) 6, P9, P14 and P21.
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Project description:Primary and secondary cone photoreceptor cell death in retinal degenerative diseases, including age-related macular degeneration and retinitis pigmentosa, leads to severe vision impairment and blindness. Regardless of the fact that protection of cone photoreceptor cells under stress conditions, such as retinal degenerative diseases, is crucial for maintaining vision, the underlying molecular mechanisms are unclear. Here, we investigated the function of the deubiquitinase Otud7b/Cezanne in the retina. We identified that Otud7b is predominantly expressed in photoreceptor cells in the mouse retina. While the ablation of Otud7b did not cause a significant defect in development and maturation of the mouse retina, Otud7b‒/‒ mice subjected to light-induced damage, which is one of the dry age-related macular degeneration models, exhibited increased cone photoreceptor degeneration. In addition, Otud7b deficiency in Mak‒/‒ mice, a retinitis pigmentosa mouse model, resulted in further cone photoreceptor degeneration. Moreover, neuronal cells deficient in Otud7b were susceptible to serum starvation, resulting in cell death. We found that NF-κB activity is increased in the Otud7b‒/‒ retinas exposed to light by RNA-sequencing analysis. Luciferase reporter assay also demonstrated increased NF-κB activation in Otud7b-deficient neuronal cells under stress. The neuronal cell death resulting from Otud7b deficiency was suppressed through the inhibition of NF-κB. Furthermore, we observed that inhibition of NF-κB attenuated cone photoreceptor degeneration in the light-exposed Otud7b‒/‒ retina. Together, the current study suggests that Otud7b deubiquitinase protects cone photoreceptor cells under stress conditions by modulating the NF-κB activity.
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Project description:Retinal degeneration is a collection of devastating conditions with progressive loss of vision which often lead to blindness. Research on retinal microglial cells offers great therapeutic potential in deterring the progression of the condition. This study explored the mechanisms underlying the TREM2-mediated protective function of activated microglial cells during retinal degeneration. A significant upregulation of disease-associated microglia signature genes was observed during photoreceptor degeneration.
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Project description:Epigenetic adaptation prolongs photoreceptor survival during retinal degeneration
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Project description:Inherited retinal diseases (IRDs) are clinically and genetically heterogeneous disorders characterized by progressive photoreceptor degeneration and irreversible vision loss. MicroRNAs (miRNAs), a class of endogenous non-coding RNAs with post-transcriptional regulatory properties, are known to play a major role in retinal function, both in physiological and pathological conditions. Given their ability to simultaneously modulate multiple molecular pathways, miRNAs represent promising therapeutic tools for disorders with high genetic heterogeneity, such as IRDs. In the present study, we performed high-content imaging (HCI) screening to assess the impact of miRNA overexpression on a photoreceptor cell line undergoing light-induced degeneration. More than 1,200 miRNAs were assayed for putative protective effects in light-stressed 661W photoreceptor-like cells, and the top-performing miRNAs were further validated in independent in vitro assays. miR-429 showed the strongest cell-protective effect in vitro. Adeno-associated viral vector-mediated subretinal delivery of miR-429 in the Rho P23H/+ IRD mouse model preserved electrophysiological responses and was associated with reduced inflammatory processes in the retina. We demonstrate that the HCI in vitro assay we devised is a reliable screening method to select candidate molecules for mutation-independent therapeutic approaches for retinal disorders. Moreover, our data indicate that miR-429 represents a potential therapeutic target against photoreceptor degeneration.
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Project description:Photoreceptor degeneration is the central event leading to visual impairment or blindness in most retinal diseases. However, the discovery of safe and effective therapeutic strategies conferring photoreceptor protection remains challenging. A systems pharmacology approach, synergistically targeting distinct cellular pathways could provide an effective strategy for evaluating, preventing or treating retinal dystrophies. Here this concept was investigated using a mouse model of light-induced retinal degeneration. We show that a combination of FDA-approved drugs acting on different G protein-coupled receptors in a synergistic manner could protect retinas against light-induced degeneration when each drug in the combination treatment was administered at a sub-therapeutic dose. Furthermore, transcriptome analyses demonstrated that such combined treatments also preserved patterns of retinal gene expression more characteristic of the normal retina than did single therapies at higher doses. The current study thus supports a new systems pharmacology approach that may extend to other complex neurodegenerative disorders in addition to retinal diseases.
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