Dr Weiyong Shen
Clinical Ophthalmology & Eye Health, Central Clinical School
Save Sight Institute
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Dr Weiyong Shen is a medical graduate who was fully trained in Clinical Ophthalmology (China). He has 8-year experience in Clinical Ophthalmology and 18-year experience in Ophthalmology and Neuroscience research.Dr Shencompletedhis PhD with a distinction award from the University of Western Australia in 2004. After working in a pharmaceutical company as a Senior Scientist for ~2 years,he returned to Australia to join the University of Sydney in 2007. He has published61 papers (21 as senior author), with 17 papers in the past 5 years. Withhis medical background and broad knowledge in Clinical Ophthalmology,Dr. Shen hasextensive experience and well-established skills in modelling retinal diseases. Hehasrecently produced a novel transgenic model in which Müller cells can be specifically targeted using a Müller cell-specific promoter along with the Cre-Lox system (Shen et al., J Neurosci 2012). This novel transgenic model has successfully attracted 2 NHMRC project grants (2012-2014, 2013-2015) and a number of grants from the Ophthalmic Research Institute of Australia (ORIA) and Rebecca Cooper Medical Research Foundation etc.Hecontributed to $4.27M research funding since 2008, including $2.01M from competitive funding bodies (3 NHMRC project grants, 4 ORIA and 2 Rebecca Cooper grants etc) and $2.26M from the Lowy Medical Research Institute and Pharmaceutical Industry. Overhis research career, Dr Shen hasestablished/been involved in 8 international and 5 national collaborations (US, United Kingdom, Sweden, Italy, Singapore and China; Universities of Queensland, Western Australia, Tasmania and Sydney), with6 current ongoing collaborations (2 international and 4 national).
- Glia-neuron-vascular interactions
- glucose metabolism and energy supply
- Selective gene knockdown using the Cre-LoxP system
- Retinal degenerations
- Diabetic retinopathy
- Age-related macular degeneration
- Pathogenesis of Macular Telangiectasis (MacTel project)
- Neuroprotection and inhibition of retinal vascular pathology in animal models
- Gene therapy and stem cell therapy for retinal diseases
Teaching and supervision
Neuroscience, Ophthalmology and Visual Science
Projects Currently Directed:
Müller glia-neuron-vascular interactions after selective Müller cell knockout
Possibly because they are invisible to clinical examination, the role of Müller cells in the pathogenesis of retinal diseases is very poorly understood. Providing the main nutritional and regulatory support to retinal neurons and vascular cells, Müller cells are both a target and a potential key player in retinal diseases such as diabetic retinopathy, macular telangiectasia type 2 and retinal veno-occlusive disease. Precisely how Müller cell dysfunction results in retinal neuronal damage and blood-retinal barrier breakdown has not yet been established. We have generated an inducible transgenic line in which a Müller cell-specific promoter along with a Cre/Lox-P approach was used for Müller cell-specific gene targeting (Figure 1A). Crossing this transgenic line into transgenic mice carrying an attenuated form of the diphtheria toxin fragment A (DTA176) gene led to conditional Müller cell ablation, which was followed by photoreceptor apoptosis, blood-retinal barrier breakdown, microglial activation and, later, intraretinal neovascularisation (Figure 1B-H). We have used this unique transgenic model to study the cellular and molecular mechanisms underlying Müller glia-neuron-vascular interactions, and also to test novel strategies for neuroprotection and inhibition of blood-retinal barrier breakdown.
The contribution of Müller cell-mediated glucose metabolism to retinal health and disease
The retina is the most metabolically active tissue in the human body. Metabolic dysfunction is a potential cause of photoreceptor death and regulation of retinal metabolism delays retinal degenerations. Müller cells are key regulators of neuronal nutrition and metabolism in the retina. However, precisely how metabolic derangement that might occur as a result of Müller cell dysfunction contributes to retinal pathology is still poorly understood. In this project, we use our unique transgenic model to profile differential expression of metabolic genes and examine changes in retinal metabolome after selective Müller cell ablation. In addition, we are currently crossing our transgenic mice with transgenic mice carrying floxed genes which are critical for glucose metabolism. This approach will produce gene knockout mice in which glucose metabolism can be specifically and inducibly disrupted in Müller cells. This project will provide fundamental information about the role of Müller cells in retinal glucose metabolism and energy supply.
The role of TLR-mediated neuroinflammation in retinal disease
Neurodegeneration and vasculopathy are features of many retinal diseases, which are often accompanied by activation of microglia and macrophages. Exaggerated inflammatory response is now thought to contribute significantly to, or even trigger, neuronal apoptosis and retinal vascular changes. The discovery of pattern recognising receptors, such as Toll-like receptors (TLRs) revolutionized our understanding of the immune system. Recent studies reveal that TLRs are involved in non-infectious diseases and injury of the central nervous system. Currently the role of TLR signaling activation in retinal diseases remains poorly understood. Our recent studies showed that photoreceptor degeneration and retinal vascular pathology are associated with microglial activation during the disease process caused by selective Müller cell ablation (Shen et al. J Neuroinflammation 2013. URL: http://www.ncbi.nlm.nih.gov/pubmed/24224958; Shen et al. Glia 2014. URL:http://www.ncbi.nlm.nih.gov/pubmed/24687761). In this project, we study the contribution of TLR-mediated neuroinflammation to retinal pathology by examination of changes in microglia, macrophages and TLR signaling over the evolution of retinal pathology caused by Müller cell ablation. We also evaluate the beneficial effects of various pharmacological approaches that target activated microglia and macrophages as well as TLR adaptor proteins. This study has genuine potential to identify new leads for the treatment of retinal diseases associated with neuroinflammation.
Differential expression of microRNAs in a murine model of selective Müller cell ablation
MicroRNAs (miRNA) are small non-coding RNAs, which can modulate post-transcriptional gene expression. They modify their target gene expression by partial or full anti- sense mechanism in the 3’ untranslated region of the target genes, and modulate protein expression. miRNAs have been recognized as a major level of post-transcriptional regulation of the fine-tuning of gene expression, playing important roles in cellular proliferation, differentiation, and cell death and are involved in all aspects of the biological processes investigated thus far. Dysregulation of miRNAs has been shown in many diseases such as cancer, cardiovascular, and neurodegenerative diseases. Recent studies have revealed important roles of miRNAs in neuronal degenerations and retinal vascular diseases. Here, we are looking into the role of miRNAs in the pathogenesis of retinal degeneration associated with glia dysfunction. We draw a particular attention to differential expression of miRNAs during photoreceptor degeneration and vascular pathology caused by selective Müller cell ablation in our transgenic model.
The impacts of altered oxygen levels on retinal pathology in Müller cell knockout mice
Vision loss due to various forms of photoreceptor degeneration remains a major problem in Ophthalmology. Most retinal degenerations are precipitated by genetic mutations affecting the retinal pigment epithelium and sensory retina, but it is becoming increasingly evident that resultant metabolic changes within the retina may also contribute to the further progression of photoreceptor cell loss. In particular, a role for the local oxygen environment within the retina has been proposed. Among different types of retinal neurons, the photoreceptors possess the highest rates of glycolysis and respiration. When photoreceptors are synaptically active, Müller cells are required to metabolize increased extracellular glutamate levels, which results in a series of biochemical reactions that stimulate glycolysis. It is generally believed that most of the energy and nucleotides required for phototransduction are provided by the metabolically active inner segments which contain abundant mitochondria and creatine kinase for ATP production. In this project, we study the impacts of altered oxygen levels on photoreceptor degeneration and retinal vascular pathology caused by selective Müller cell ablation.
Projects Currently Involved:
The contribution of aberrant Wnt signalling to neuronal and vascular pathology in retinal disease
Neuronal damage and vascular pathology, both of which are potentially associated with glial dysfunction, are features shared by many retinal diseases. Aberrant Wnt signalling plays opposing roles in these 2 processes: activation of Wnt signalling promotes vascular leak and neovascularisation but it also exerts a trophic effect on neurons. As selective Müller cell ablation in our transgenic mice leads to photoreceptor apoptosis, blood-retinal barrier breakdown and, later, deep retinal neovascularisation, we use this unique model to study changes in the canonical Wnt signalling pathway as retinal neural and vascular changes progress over time. We also study the effects of inhibition of Wnt signalling on both processes and test whether supplementing neurotrophic factor with Wnt inhibitors protects neurons while still suppressing retinal vasculopathy.
Dysregulation of interphotoreceptor retinoid binding protein in the pathogenesis of retinal disease
Aberrant visual cycle caused by dysregulationof interphotoreceptor retinoid binding protein(IRBP, also termed Retinol-binding protein 3) is a potential major lead of many retinal diseases. Using the Müller cell knockout model, we recently found that secreted signals/factors from Müller cells might be critical for the maintenance of a proper level of IRBP in the retina. However, the detailed molecular mechanisms underlying IRBP dysregulation and its contribution to retinal pathology remain unclear. Taking advantage of the selective Müller cell ablation transgenic mouse model, we explore the causal relationship between Müller cell dysfunction and IRBP deficiency. Effort is being taken to identify and validate the signalling factors secreted from Müller cells that may regulate IRBP expression. We also evaluate the therapeutic effectiveness of compensating IRBP deficiency.
The use of patient derived induced pluripotent stem cells in modelling of MacTel type 2
Induced pluripotent stem cells (iPSc) are a type of stem cells reprogrammed from somatic cells such as primary fibroblasts from patient biopsy samples. iPSc behave like embryonic stem cells, such that, they can grow indefinitely while maintaining pluripotency and differentiate into any types of cells in the body. Unlike stem cells, however, iPSc avoid ethical concerns and immunologic barriers when transplanted into patients. iPSc research possesses great potentials in personalised and regenerative medicine. For example, they can be used in disease modelling for drug test in pharmaceutical industry, and also be transplanted into patients after gene correction (if there is a known gene defect). This project aims to model Macular Telangiectasis Type 2 (MacTel-2) in a dish using iPSc reprogrammed from patient biopsy samples. We are particularly interested in driving iPSc to differentiate into Müller cells and then candidate genes potentially associated with the pathogenesis of MacTel-2.
PhD and master's project opportunities
(Prof James Hurley, Department of Biochemistry, University of Washington.)
Current collaboration with Prof. Hurley's group is to analyze changes in retinal metabolites and flux through retinas after selective ablation of Muller cells and conditional knockdown of metabolic genes in Muller cells using transgenic models for Muller cell-specific gene targeting.
(Prof. Joshua L. Dunaief, Scheie Eye Institute, Harvard Medical School. )
This collaborative project is to study the role of Muller cells in retinal iron regulation using a transgenic model in which Muller cells can be inducibly and selectively ablated.
- Understanding the role of microglia in retinal health and disease; Shen W; Ophthalmic Research Institute of Australia (ORIA)/Research Grant.
- The contribution of aberrant Wnt signalling to neuronal and vascular pathology in retinal disease; Gillies M, Shen W, McAvoy J, Zhu L; National Health and Medical Research Council (NHMRC)/Project Grants.
- Neuroprotection and anti-angiogenic therapy using a novel transgenic model; Shen W, Zhu L; Ophthalmic Research Institute of Australia (ORIA)/Research Grant.
- Glial-neuronal-vascular interactions in a novel transgenic model of Muller cell dysfunction; Gillies M, Shen W, Barnett N; National Health and Medical Research Council (NHMRC)/Project Grants.
- Regulation of bone marrow progenitor cells for diabetic retinopathy; Gillies M, Shen W; National Health and Medical Research Council (NHMRC)/Project Grants.
- Gilal dysfunction in diabetic retinopathy; Shen W; Ophthalmic Research Institute of Australia (ORIA)/Research Grant.
- Regulation of bone marrow progenitor cells for treatment of diabetic retinopathy; Shen W, Gillies M; DVC Research/Bridging Support Grant.