Role of microRNA-143, -150 and 126 in pathological retinal angiogenesis
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE139947 | GEO | 2021/10/01
REPOSITORIES: GEO
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Project description:Role of microRNA-143, -150 and 126 in pathological retinal angiogenesis
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Project description:Emerging evidence suggests a link between the circadian clock and retinopathies though the causality has not been established. Circadian clocks in the mammalian retina regulate a diverse range of retinal functions that allow the retina to adapt to the light-dark cycle. We report that clock genes are expressed in the embryonic retina, and the embryonic retina requires light cues to maintain robust circadian expression of the core clock gene, Bmal1. Deletion of Bmal1 and Per2 from the retinal neurons results in retinal angiogenic defects similar to when animals are maintained under constant light conditions. Using two different models to assess pathological neovascularization, we show that neuronal Bmal1 deletion reduces neovascularization with reduced vascular leakage, suggesting that a dysregulated circadian clock primarily drives neovascularization. Chromatin immunoprecipitation sequencing analysis suggests that semaphorin signaling is the dominant pathway regulated by Bmal1. Our data indicate that therapeutic silencing of the retinal clock could be a common approach for the treatment of certain retinopathies like diabetic retinopathy and retinopathy of prematurity.
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Project description:Pathologic retinal neovascularization is a potentially blinding consequence seen in many common diseases including diabetic retinopathy, retinopathy of prematurity, and retinal vascular occlusive diseases, among others. The use of therapeutics targeting pro-angiogenesis factors such as vascular endothelial growth factor (VEGF) has proven to be highly effective, however considerable side effects exist and serial anti-VEGF treatment has been shown to decrease effectiveness over time. Characterization of additional regulators of neovascularization is needed to further understand neovascular disease and identify possible new therapeutic targets. This study investigates epithelial membrane protein 2 (EMP2) and its role as a possible modulator of angiogenesis in human retinal pigment epithelium (RPE) under hypoxia. EMP2 is highly expressed in human RPE and RPE cell lines. Adult retinal pigment epithelial cell line-19 (ARPE-19) cells were genetically modified to either overexpress EMP2 (OE) or knock down EMP2 (KD) and expression at the RNA and protein level was evaluated using RNA sequencing and western blot respectively. Protein expression was evaluated under both normoxic conditions and conditions of hypoxic stress with 0.5% O2. EMP2 expression was found to positively correlate with expression of the pro-angiogenesis factors hypoxia inducible factor 1-alpha (HIF-1a) and VEGF for both RNA and protein. EMP2 mediated changes in ARPE-19 cells was also found to alter the secretion of a paracrine factor(s) in conditioned media that can regulate human umbilical vein endothelial cells (HUVEC) endothelial cell migration and capillary tube formation in in vitro functional angiogenesis assays. This study identifies EMP2 as a potentially important mediator of angiogenesis in the human RPE, a tissue involved in abnormal retinal neovascularization in a number of diseases. EMP2 levels positively correlate with those of the potent pro-angiogenesis mediators HIF-1a and VEGF, however the mechanism of this relationship remains to be clarified. This study supports further investigation of EMP2 as a promising novel target for therapeutic treatment of pathologic neovascularization in the retina.
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Project description:Retinopathy of prematurity (ROP) is a leading cause of childhood blindness, and exclusively affects infants born prematurely. In this study, we test the hypothesis that EMP2 contributes to neovascularization in a mouse model of the disease. We show that EMP2 promotes neuronal VEGF signaling and that its downregulation reduces severity of neovascularization.
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Project description:The purpose of this study is to identify disease-related miRNAs in retinas of a mouse model of oxygen-induced retinopathy (OIR). OIR pups were exposed to 75% oxygen at postnatal day (P)7 for 5 days, and were returned to room air at P12. The miRNAs expression profiles in the retinas from OIR mice at P17 and room air controls were determined through microarray analysis. Expressions of significantly upregulated and downregulated miRNAs in the OIR retinas and controls were confirmed through quantitative real-time RT-PCR (qPCR). Compared to the room air controls, 3 miRNAs were significantly up-regulated, and 8 miRNAs were down-regulated in OIR retinas. Our findings indicated that several miRNAs were differentially expressed in the oxygen-induced retinal neovascularization, which might provide novel therapeutic targets in regulating retinal neovascular diseases.
2018-06-19 | GSE115949 | GEO
Project description:In order to find out the vital genes during retinal neovascularization (RNV), we set up OIR (oxygen-induced retinopathy; induced with 75%±2% oxygen) and wild-type C57BL/6J murine models. We observed the retinal vascular growth process daily both in OIR and wild-type mice through retinal flat-mount, and isolated total retinal RNA at different time points (P8, P9, P12, P13, P30) both in OIR and wild-type mice for gene expression analysis. At least three different retinae were accessed at each time point for observing the retinal vascular growth process. Ten neural retinae from five mice were harvested and pooled into one sample for gene expression analysis. Three biological replicates were used for each time point. Dye-swaps were performed.
2012-12-05 | E-GEOD-38762 | biostudies-arrayexpress
Project description:In order to find out the vital genes during retinal neovascularization (RNV), we set up OIR (oxygen-induced retinopathy; induced with 75%±2% oxygen) and wild-type C57BL/6J murine models. We observed the retinal vascular growth process daily both in OIR and wild-type mice through retinal flat-mount, and isolated total retinal RNA at different time points (P8, P9, P12, P13, P30) both in OIR and wild-type mice for gene expression analysis.
2012-12-05 | GSE38762 | GEO