Optometry and Vision Sciences - Research Publications

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Type: Preprint × Author: van Wijngaarden, Peter ×

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    MicroRNA-143 plays a protective role in ischemia-induced retinal neovascularization
    Wang, J-H ; Chen, J ; Ling, D ; Tu, L ; Singh, V ; Riaz, M ; Li, F ; Prea, SM ; He, Z ; Bui, BV ; Hewitt, AW ; van Wijngaarden, P ; Dusting, GJ ; Liu, G-S ( 2019-02-13)
    Retinal neovascularization is a severe complication of proliferative diabetic retinopathy. MicroRNAs (miRNAs) are master regulators of gene expression that play important roles in retinal neovascularization. Here, we investigated the retinal miRNA expression profile in a rat model of oxygen-induced retinopathy (OIR) through miRNA-Seq. We found that miR-143-3p, miR-126-3p, miR-150-5p and miR-145-5p were significantly down-regulated in the retina of OIR rats, and directly involved in the development of retinal neovascularization. Of these identified miRNAs, miR-143 is enriched in retina and was first reported being associated with pathological retinal angiogenesis. Our RNA-Seq data further suggested that miR-143 alleviates retinal neovascularization by mediating the inflammation/stress pathways via Fos. Moreover, the computational analysis indicated that Transforming Growth Factor-beta Activated Kinase 1 (TAK1) is involved in several key pathways associated with the dysregulated miRNAs. The pharmacological inhibition of TAK1 suppressed angiogenesis in vitro and retinal neovascularization in vivo. Our data highlight the utility of next-generation sequencing in the development of therapeutics for ocular neovascularization and further suggest that therapeutic targeting the dysregulated miRNAs or TAK1 may be a feasible adjunct therapeutic approach in patients with retinal neovascularization.
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    TAK1 blockade as a therapy for retinal neovascularization
    Lin, F-L ; Wang, J-H ; Chen, J ; Zhu, L ; Chuang, Y-F ; Tu, L ; Ma, C ; Lama, S ; Ling, D ; Wong, RC-B ; Hewitt, A ; Tseng, C-L ; Bui, B ; van Wijngaarden, P ; Dusting, G ; Wang, P-Y ; Liu, G-S ( 2021-01-29)
    Retinal neovascularization, or pathological angiogenesis in the retina, is a leading cause of blindness in developed countries. Transforming growth factor-β-activated kinase 1 (TAK1) is a mitogen-activated protein kinase kinase kinase (MAPKKK) activated by TGF-β1 and other pro-inflammatory cytokines. TAK1 is also a key mediator of inflammation, innate immune responses, apoptosis and tissue homeostasis and plays an important role in physiological angiogenesis. Its role in pathological angiogenesis, particularly in retinal neovascularization, remains unclear. We investigated the regulatory role of TAK1 in pathological angiogenesis in the retina. Transcriptome analysis of human retina featuring retinal neovascularization revealed enrichment of known TAK1-mediated signaling pathways. Selective inhibition of TAK1 activation by 5Z-7-oxozeaenol attenuated aberrant retinal angiogenesis in rats following oxygen-induced retinopathy. Transcriptome profiling revealed that TAK1 activation in human microvascular endothelial cells under TNFα stimulation led to increase the gene expression related to cytokines and leukocyte-endothelial interaction, mainly through nuclear factor kappa B (NFκB) signaling pathways. These results reveal that inhibition of TAK1 signaling may have therapeutic value for the treatment of pathological angiogenesis in the retina.