ORCID Profile
0000-0002-1551-9660
Current Organisation
Centre for Eye Research Australia
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Publisher: Cold Spring Harbor Laboratory
Date: 04-04-2022
DOI: 10.1101/2022.04.03.22273375
Abstract: Age is the main risk factor for age-related macular degeneration (AMD), a leading cause of blindness in the elderly, with limited therapeutic options. Here we systematically analyzed the transcriptomic characteristics and cellular landscape of the aging retina from controls and patients with AMD. We identify the aging genes in the retina that are associated with innate immune response and inflammation. Deconvolution analysis reveals that the estimated proportion of M2 and M0 macrophages is increased and decreased, respectively with both age and AMD severity. Moreover, we find that Müller glia are increased with age but not with disease severity. Several genes associated with both age and disease severity in AMD, particularly C1s and MR1 , are strong positively correlated with the proportions of Müller glia. Our studies expand the genetic and cellular landscape of AMD and provide avenues for further studies on the relationship between age and AMD.
Publisher: Cold Spring Harbor Laboratory
Date: 29-01-2021
DOI: 10.1101/2021.01.29.428701
Abstract: 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.
Publisher: Informa UK Limited
Date: 25-02-2021
Publisher: Cold Spring Harbor Laboratory
Date: 10-05-2022
DOI: 10.1101/2022.05.05.22274746
Abstract: Previous studies identify putative genes associated with diabetic retinopathy only focusing on specific clinical stage, thus resulting genes are not necessarily reflective of disease progression. To identify genes associated with the severity level of diabetic retinopathy using likelihood-ration test (LRT) and ordinal logistic regression (OLR) model, as well as to profile immune and retinal cell landscape in progressive diabetic retinopathy using a machine learning deconvolution approach. This study used published transcriptomic dataset (GSE160306) from macular regions of donors with different degrees of diabetic retinopathy (10 healthy controls, 10 cases of diabetes, 9 cases of nonproliferative diabetic retinopathy and 10 cases of proliferative diabetic retinopathy or combined with diabetic macular edema). Transcriptomic dataset was released on April 19, 2021 data were analyzed on 28th March 2022. Identification of severity-associated genes with LRT and OLR model and proportional changes of immune and retinal cells in progressive diabetic retinopathy. By controlling for gender and age using LRT and OLR, 50 genes were identified to be significantly increased in expression with the severity of diabetic retinopathy. Functional enrichment analyses suggested these severity-associated genes are related to inflammation and immune responses. CCND1 and FCGR2B are further identified as key regulators to interact with many other severity-associated genes and are crucial to inflammation. Deconvolution analyses demonstrated that the proportions of memory B cells, M2 macrophages and Müller glia were significantly increased with the progression of diabetic retinopathy. These findings demonstrate the deep analyses of transcriptomic data can advance our understanding of progressive ocular diseases, such as DR, by applying LRT and OLR model as well as bulk gene expression deconvolution. Do genes change in expression or immune cells and retinal cells change in proportions in the human retina with the severity of diabetic retinopathy? In this in-depth retinal transcriptomic analysis of 39 participants, consisting of 10 heathy controls, 29 cases of diabetic retinopathy at different clinical stages, severity-associated genes were identified, and the estimated proportions of immune cell and retinal cells were profiled, respectively. These findings demonstrate that a group of genes are significantly increased in expression, and the proportions of memory B cells, M2 macrophages and Müller glia were significantly increased with the severity of diabetic retinopathy.
Publisher: Elsevier BV
Date: 2019
Publisher: Informa UK Limited
Date: 02-03-2021
Publisher: Mary Ann Liebert Inc
Date: 08-2022
Abstract: Retinal neovascularization is a severe complication of proliferative diabetic retinopathy (PDR). MicroRNAs (miRNAs) are master regulators of gene expression that play an important role in retinal neovascularization. In this study, we show that miR-143-3p is significantly downregulated in the retina of a rat model of oxygen-induced retinopathy (OIR) by miRNA-sequencing. Intravitreal injection of synthetic miR-143 mimics significantly ameliorate retinal neovascularization in OIR rats. miR-143 is identified to be highly expressed in the neural retina particularly in the ganglion cell layer and retinal vasculature. In miR-143 treated cells, the functional evaluation showed a decrease in cell migration and delayed endothelial vessel-like tube remodeling. The multiomics analysis suggests that miR-143 negatively impacts endothelial cell activity through regulating cell-matrix adhesion and mediating hypoxia-inducible factor-1 signaling. We predict hub genes regulated by miR-143 that may be involved in mediating endothelial cell function by cytoHubba. We also demonstrate that the retinal neovascular membranes in patients with PDR principally consist of endothelial cells by CIBERSORTx. We then identify 2 hub genes, thrombospondin 1 and plasminogen activator inhibitor, direct targets of miR-143, that significantly altered in the PDR patients. These findings suggest that miR-143 appears to be essential for limiting endothelial cell-matrix adhesion, thus suppressing retinal neovascularization.
No related grants have been discovered for Jiang-Hui Wang.