Optometry and Vision Sciences - Research Publications

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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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    Progressive impairments in executive function in the APP/PS1 model of Alzheimer’s disease as measured by translatable touchscreen testing
    Shepherd, A ; Lim, JKH ; Wong, VHY ; Zeleznikow-Johnston, AM ; Churilov, L ; Nguyen, CTO ; Bui, BV ; Hannan, AJ ; Burrows, EL ( 2019-08-21)
    Executive function deficits in Alzheimer’s disease (AD) occur early in disease progression and may be predictive of cognitive decline. However, no preclinical studies have identified deficits in rewarded executive function in the commonly used APP/PS1 mouse model. To address this, we assessed 12-26 month old APP/PS1 mice on rewarded reversal and/or extinction tasks. 16-month-old, but not 13- or 26-month-old, APP/PS1 mice showed an attenuated rate of extinction. Reversal deficits were seen in 22-month-old, but not 13-month-old APP/PS1 animals. We then confirmed that impairments in reversal were unrelated to previously reported visual impairments in both AD mouse models and humans. Age, but not genotype, had a significant effect on markers of retinal health, indicating the deficits seen in APP/PS1 mice were directly related to cognition. This is the first characterisation of rewarded executive function in APP/PS1 mice, and has great potential to facilitate translation from preclinical models to the clinic.
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    Targeted Delivery of Lm22a-4 by Cubosomes Protects Retinal Ganglion Cells in an Experimental Glaucoma Model
    Ding, Y ; Chow, SH ; Chen, J ; Le Brun, AP ; Wu, C-M ; Duff, AP ; Wang, Y ; Wong, VHY ; Zhao, D ; Lee, T-H ; Conn, CE ; Hsu, H-Y ; Bui, BV ; Liu, G-S ; Shen, H-H ( 2020-01-01)
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    Fractalkine-induced microglial vasoregulation occurs within the retina and is altered early in diabetic retinopathy
    Mills, S ; Jobling, A ; Dixon, M ; Bui, B ; Vessey, K ; Phipps, J ; Greferath, U ; Venables, G ; Wong, VHY ; Wong, CHY ; He, Z ; Hui, F ; Young, J ; Tonc, J ; Ivanova, E ; Sagdullaev, B ; Fletcher, E ( 2020)
    Local blood flow control within the CNS is critical to proper function and is dependent on coordination between neurons, glia and blood vessels. Macroglia such as astrocytes and Müller cells, contribute to this neurovascular unit within the brain and retina, respectively. This study explored the role of microglia, the innate immune cell of the CNS, in retinal vasoregulation and highlights changes during early diabetes. Structurally, microglia were found to contact retinal capillaries and neuronal synapses. In the brain and retinal explants, the addition of fractalkine, the sole ligand for monocyte receptor Cx3cr1, resulted in capillary constriction at regions of microglial contact. This vascular regulation was dependent on microglial involvement, since mice lacking Cx3cr1, exhibited no fractalkine-induced constriction. Analysis of the microglial transcriptome identified several vasoactive genes, including angiotensinogen, a constituent of the renin-angiotensin system (RAS). Subsequent functional analysis showed that RAS blockade via candesartan, abolished microglial-induced capillary constriction. Microglial regulation was explored in a rat streptozotocin (STZ) model of diabetic retinopathy. Retinal blood flow was reduced after 4 weeks due to reduced capillary diameter and this was coincident with increased microglial association. Functional assessment showed loss of microglial-capillary response in STZ-treated animals and transcriptome analysis showed evidence of RAS pathway dysregulation in microglia. While candesartan treatment reversed capillary constriction in STZ-treated animals, blood flow remained decreased likely due to dilation of larger vessels. This work shows microglia actively participate in the neurovascular unit, with aberrant microglial-vascular function possibly contributing to the early vascular compromise during diabetic retinopathy.

    Significance Statement

    This work identifies a novel role for microglia, the innate immune cells of the CNS, in the local control of the retinal vasculature and identifies deficits early in diabetes. Microglia contact neurons and vasculature and express several vasoactive agents. Activation of microglial fractalkine-Cx3cr1 signalling leads to capillary constriction and blocking the renin-angiotensin system (RAS) with candesartan abolishes microglial-mediated vasoconstriction in the retina. In early diabetes, reduced retinal blood flow is coincident with capillary constriction, increased microglial-vessel association, loss of microglial-capillary regulation and altered microglial expression of the RAS pathway. While candesartan restores retinal capillary diameter early in diabetes, targeting of microglial-vascular regulation is required to prevent coincident dilation of large retinal vessels and reduced retinal blood flow.
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    Altered visual function in a larval zebrafish knockout of neurodevelopmental risk gene
    Xie, J ; Jusuf, PR ; Bui, BV ; Dudczig, S ; Goodbourn, PT ( 2020-09-22)
    The human PDZK1 gene is located in a genomic susceptibility region for neurodevelopmental disorders. A genome-wide association study (GWAS) identified links between PDZK1 polymorphisms and altered visual contrast sensitivity, an endophenotype for schizophrenia and autism spectrum disorder. The PDZK1 protein is implicated in neurological functioning, interacting with synaptic molecules including post-synaptic density 95 (PSD-95), N-methyl-D-aspartate receptors (NMDAR), corticotropin-releasing factor receptor 1 (CRFR1) and serotonin 2A receptors. To elucidate the role of PDZK1, we generated pdzk1-knockout (pdzk1-KO) zebrafish using CRISPR/Cas-9 genome editing. Visual function of 7-day-old fish was assessed at behavioural and functional levels using the optomotor response (OMR) and scotopic electroretinogram (ERG). We also quantified retinal morphology and densities of PSD-95, NMDAR1, CRFR1 and serotonin in the synaptic inner plexiform layer at 7 days, 4 weeks and 8 weeks of age. Relative to wild-type, pdzk1-KO larvae showed spatial-frequency tuning functions with increased amplitude (likely due to abnormal gain control) and reduced ERG b-waves (suggestive of inner retinal dysfunction). However, these functional differences were not associated with gross synaptic or morphological retinal phenotypes. The findings corroborate a role for pdzk1 in visual function, and our model system provides a platform for investigating other genes associated with abnormal visual behaviour.
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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.
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    Targeted delivery of LM22A-4 by cubosomes protects retinal ganglion cells in an experimental glaucoma model
    Ding, Y ; Chow, SH ; Chen, J ; Le Brun, AP ; Wu, C-M ; Duff, AP ; Wang, Y ; Wong, VHY ; Zhao, D ; Lee, T-H ; Conn, CE ; Hsu, H-Y ; Bui, B ; Liu, G-S ; Shen, H-H (SSRN, 2021-04-29)
    Glaucoma, a major cause of irreversible blindness worldwide, is associated with elevated intraocular pressure (IOP) and progressive loss of retinal ganglion cells (RGCs) that undergo apoptosis. A mechanism for RGCs injury involves impairment of neurotrophic support and exogenous supply of neurotrophic factors has been shown to be beneficial. However, neurotrophic factors can have widespread effects on neuronal tissues, thus targeting neurotrophic support to injured neurons may be a better neuroprotective strategy. In this study, we have encapsulated LM22A-4, a small neurotrophic factor mimetic, into Annexin V-conjugated cubosomes (L4-ACs) for targeted delivery to injured RGCs in a model of glaucoma, which is induced by acute IOP elevation. We have tested cubosomes formulations that encapsulate from 9% to 33% LM22A-4. Our data indicated that cubosomes encapsulating 9% and 17% LM22A-4 exhibited a mixture of Pn3m/Im3m cubic phase, whereas 23% and 33% showed a pure Im3m cubic phase. We found that 17% L4-ACs with Pn3m/Im3m symmetries showed better in-situ and in-vitro lipid membrane interactions than the 23% and 33% L4-ACs with Im3m symmetry. In vivo experiments showed that 17% L4-ACs targeted the posterior retina and the optic nerve head, which prevented RGCs loss in a mouse model of acute IOP elevation. These results provide evidence that cubosomesbased LM22A-4 delivery may be a useful targeted approached to prevent the progression of RGCs loss in glaucoma.