J V Forrester

University of Western Australia, Perth City, Western Australia, Australia

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Publications (346)1203.72 Total impact

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    ABSTRACT: Macrophage adherence to the inner corneal surface and formation of MGCs in the stroma are common signs of chronic inflammation following corneal infection. To determine whether macrophage adherence (known clinically as KPs) and giant cell formation were specific to innate immune activation via particular TLR ligands, macrophage activation was examined in a murine model of TLR-mediated corneal inflammation. The corneal epithelium was debrided and highly purified TLR ligands were topically applied once to the cornea of TLR7(-/-), TLR9(-/-), Cx3cr1(gfp/+), CD11c(eYFP), and IL-4(-/-) mice. At 1 week post-treatment macrophage activation and phenotype was evaluated in the cornea. Treatment with TLR2, TLR3, TLR4, and TLR5 ligands caused an increase in the number of activated stromal macrophages in the central cornea at 1 week post-treatment. However, treatment with TLR9 ligand CpG-ODN and the TLR7/8 ligand R848/Resiquimod led to an accumulation of macrophages on the corneal endothelium and formation of multinucleated giant macrophages in the corneal stroma. We suggest that giant cell formation, which is a characteristic feature of granuloma formation in many tissues, may be a unique feature of TLR9- and TLR7/8-mediated macrophage activation. © Society for Leukocyte Biology.
    Journal of leukocyte biology. 11/2014;
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    ABSTRACT: Corneal graft rejection is primarily a CD4(+) T cell-mediated mechanism in which macrophages may play an important inflammatory role. CD200Fc fusion protein is an artificial agonist of CD200R1, a receptor expressed predominantly on myeloid cells, engagement of which is known to down-regulate macrophage function. We therefore wished to test whether CD200Fc could be used as a therapeutic agent to prolong corneal graft survival. The distribution of CD200R1 and CD200, its natural ligand, was examined by immunohistology in the cornea and conjunctiva of unoperated rats and rats that had received corneal allografts. Mouse CD200Fc was injected subconjunctivally into transplanted rats on six occasions from the day of surgery until day 10 after transplantation. Control groups received injections of mouse IgG or diluent PBS. Allo-transplants were also performed in CD200(-/-) and control mice. The ability of CD200Fc to bind rat macrophages in vitro and to inhibit nitric oxide production was tested. Mean day of rejection in CD200Fc, IgG and PBS-treated rats was 12, 10 and 9 respectively (p=0.24). Mean day of rejection in CD200(-/-) and wild type mice was 17.5 and 16.0 respectively (p=0.07). Mouse CD200Fc bound to rat macrophages in a dose-dependent manner, but was unable to inhibit nitric oxide production. The fact that treatment with CD200Fc did not inhibit graft rejection and the failure of CD200 deficiency to affect graft survival suggests that local targeting of the CD200-CD200R axis to suppress macrophage activation is not a useful therapeutic strategy in corneal graft rejection. Copyright © 2014 Elsevier Ltd. All rights reserved.
    Experimental Eye Research 11/2014; 130C:1-8. · 3.03 Impact Factor
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    ABSTRACT: Interleukin (IL)-33 is associated with several important immune-mediated disorders. However, its role in uveitis, an important eye inflammatory disease, is unknown. Here we investigated the function of IL-33 in the development of experimental autoimmune uveitis (EAU). IL-33 and IL-33 receptor (ST2) were expressed in murine retinal pigment epithelial (RPE) cells in culture, and IL-33 increased the expression of Il33 and Mcp1 mRNA in RPE cells. In situ, IL-33 was highly expressed in the inner nuclear cells of the retina of naïve mice, and its expression was elevated in EAU mice. ST2-deficient mice developed exacerbated EAU compared with WT mice, and administration of IL-33 to WT mice significantly reduced EAU severity. The attenuated EAU in IL-33-treated mice was accompanied by decreased frequency of IFN-γ+ and IL-17+ CD4+ T cells and reduced IFN-γ and IL-17 production but with increased frequency of IL-5+ and IL-4+ CD4 T cells and IL-5 production in the draining lymph node and spleen. Macrophages from the IL-33-treated mice show a significantly higher polarization towards an alternatively-activated macrophage (M2) phenotype. Our results therefore demonstrate that the endogenous IL-33/ST2 pathway plays an important role in EAU, and suggest that IL-33 represents a potential option for treatment of uveitis.This article is protected by copyright. All rights reserved
    European Journal of Immunology 08/2014; · 4.97 Impact Factor
  • Kurt Spiteri Cornish, Lucia Kuffova, John V Forrester
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    ABSTRACT: Diffuse subretinal fibrosis uveitis (DUS) syndrome is a rare form of granulomatous multifocal choroiditis (MFC) characterised by enlarging areas of subretinal fibrosis (SRF) which coalesce with subsequent macular involvement and visual loss. First described by Palestine, DUS carries a poor visual prognosis despite use of high-dose corticosteroids and systemic immunosuppression. We report two cases of bilateral DUS successfully treated with rituximab. We believe given the B-cell predominance in the underlying pathogenesis of the disease, rituximab should be considered first line in the management of this potentially devastating disease.
    The British journal of ophthalmology. 05/2014;
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    ABSTRACT: To evaluate the potential utility of collagen-based corneal implants with anti-Herpes Simplex Virus (HSV)-1 activity achieved through sustained release of LL-37, from incorporated nanoparticles, as compared with cell-based delivery from model human corneal epithelial cells (HCECs) transfected to produce endogenous LL-37.
    Translational vision science & technology. 05/2014; 3(3):4.
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  • Zexu Dang, Lucia Kuffová, Lei Liu, John V Forrester
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    ABSTRACT: The transport of antigen to the secondary lymphoid tissue is a central component in the initiation of the adaptive immune response. The mechanism of antigen delivery to the DLN from the avascular cornea has not been fully explored. Previous studies in the mouse have shown that cell-associated corneal antigen is delivered within 6 h to the eye draining SM DLN via DCs and macrophages. In this study, we used a system in which antigen and the processed p-MHCII complexes derived from the antigen could be tracked in vivo. We report that soluble antigen applied to an abraded cornea in the mouse is transported rapidly (within 30 min) to the SM DLN, where a proportion is taken up by resident DCs and presented as p-MHCII complexes, while the larger part is cleared by 8 h. At a later time, a second wave of antigen transport in migratory DCs enters the DLN and participates in further continued antigen presentation. With the use of an antigen-specific TCR transgenic mouse system, we demonstrate that T cell activation does not occur during the early stages of soluble antigen delivery to LN, even though p-MHCII complexes are generated. Antigen-specific T cell activation occurs in the later, presumed cell-associated phase but requires codelivery of a "danger" signal, such as the TLR ligand CpG. We suggest that the early delivery of soluble antigen is more likely to induce T cell nonresponsiveness (anergy) unless presented in the context of an innate-immune cell activation (danger) signal.
    Journal of leukocyte biology 12/2013; · 4.99 Impact Factor
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    ABSTRACT: Protein-tyrosine phosphatase-1B (PTP1B) negatively regulates insulin and leptin signalling, rendering it an attractive drug target for treatment of obesity-induced insulin resistance. However, some studies suggest caution when targeting macrophage-PTP1B, due to its potential anti-inflammatory role. We assessed the role of macrophage-PTP1B in inflammation and whole body metabolism using myeloid-cell (LysM)-PTP1B-knockout mice (LysM-PTP1B). LysM-PTP1B mice were protected against LPS-induced endotoxemia and hepatic damage, associated with decreased pro-inflammatory cytokine secretion in vivo. In vitro, LPS-treated LysM-PTP1B bone-marrow-derived-macrophages (BMDMs) displayed increased IL10 mRNA expression, with a concomitant decrease in TNFα mRNA levels. These anti-inflammatory effects were associated with increased LPS- and IL10-induced STAT3 phosphorylation in LysM-PTP1B BMDMs. Chronic inflammation induced by high-fat (HF)-feeding led to equally beneficial effects of macrophage-PTP1B deficiency; LysM-PTP1B mice exhibited improved glucose- and insulin tolerance, protection against LPS-induced hyperinsulinemia, decreased macrophage infiltration into adipose tissue and decreased liver damage. HF-fed LysM-PTP1B mice had increased basal and LPS-induced IL10 levels, associated with elevated splenic STAT3 phosphorylation, IL10 mRNA expression, and expansion of cells expressing myeloid markers. These increased IL10 levels negatively correlated with circulating insulin and ALT levels. Our studies implicate myeloid-PTP1B in negative regulation of STAT3/IL10-mediated signalling, highlighting its inhibition as a potential anti-inflammatory and anti-diabetic target in obesity.
    Diabetes 11/2013; · 7.90 Impact Factor
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    ABSTRACT: We have previously shown that recombinant human collagen can be cross-linked with N-(3 - Dimethylaminopropyl)-N'-ethylcarbodiimide (EDC) to fabricate transparent hydrogels possessing the shape and dimensions of the human cornea. These corneal implants have been tested in a Phase I human clinical study. Although these hydrogels successfully promoted corneal tissue and nerve regeneration, during manufacture of the implants, the gelling kinetics were difficult to control. An alternative carbodiimide capable of producing hydrogels of similar characteristics as EDC in terms of strength and biocompatibility, but with a longer gelation time would be a desirable alternative. Here, we compared the cross-linking kinetics and properties of hydrogels cross-linked with a sterically bulky carbodiimide, N-cyclohexyl-N'-(2-morpholinethyl) carbodiimide metho-p-toluenesulfonate (CMC), with that of EDC. CMC cross-linking was possible at ambient temperature while the EDC reaction was too rapid to control and had to be carried out at low temperatures. The highest tensile strength obtained using optimized formulations were equivalent, although CMC cross-linked hydrogels were found to be stiffer. The collagenase resistance of CMC cross-linked hydrogels was superior to that of EDC crosslinked hydrogels while biocompatibility was similar. We are also able to substitute porcine collagen with recombinant human collagen and show that the in vivo performance of both resulting hydrogels as full thickness corneal implants is comparable in a mouse model of anorthotopic corneal graft. In conclusion, CMC is a viable alternative to EDC as a cross-linker for collagen-based biomaterials for use as corneal implants, and potentially for use in other tissue engineering applications.
    Acta biomaterialia 04/2013; · 5.68 Impact Factor
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    ABSTRACT: Previous studies have shown that CCL2/CX3CR1 deficient mice on C57BL/6N background (with rd8 mutation) have an early onset (6 weeks) of spontaneous retinal degeneration. In this study, we generated CCL2-/-CX3CR1GFP/GFP mice on the C57BL/6J background. Retinal degeneration was not detected in CCL2-/-CX3CR1GFP/GFP mice younger than 6 months. Patches of whitish/yellowish fundus lesions were observed in 17,60% of 12-month, and 30,100% of 18-month CCL2-/-2CX3CR1GFP/GFP mice. Fluorescein angiography revealed no choroidal neovascularisation in these mice. Patches of retinal pigment epithelium (RPE) and photoreceptor damage were detected in 30% and 50% of 12- and 18-month CCL22/ 2CX3CR1GFP/GFP mice respectively, but not in wild-type mice. All CCL22/2CX3CR1GFP/GFP mice exposed to extra-light (~800lux, 6 h/day, 6 months) developed patches of retinal atrophy, and only 20–25% of WT mice which underwent the same light treatment developed atrophic lesions. In addition, synaptophysin expression was detected in the outer nucler layer (ONL) of area related to photoreceptor loss in CCL22-/-CX3CR1GFP/GFP mice. Markedly increased rhodopsin but reduced cone arrestin expression was observed in retinal outer layers in aged CCL22/2CX3CR1GFP/GFP mice. GABA expression was reduced in the inner retina of aged CCL2-/-CX3CR1GFP/GFP mice. Significantly increased Mu¨ ller glial and microglial activation was observed in CCL22/2CX3CR1GFP/GFP mice compared to age-matched WT mice. Macrophages from CCL2-/-CX3CR1GFP/GFP mice were less phagocytic, but expressed higher levels of iNOS, IL-1b, IL-12 and TNF-a under hypoxia conditions. Our results suggest that the deletions of CCL2 and CX3CR1 predispose mice to age- and light-mediated retinal damage. The CCL2-/-CX3CR1 deficient mouse may thus serve as a model for age-related atrophic degeneration of the RPE, including the dry type of macular degeneration, geographic atrophy.
    PLoS ONE 04/2013; 8(4):e61381. · 3.53 Impact Factor
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    ABSTRACT: Since the plasticity and the potential for re-programming cells has become widely accepted, there has been great interest in cell-based therapies. These are being applied to a range of diseases, not least ocular diseases, where it is assumed that there is a reduced risk of immune rejection although this may be more perceived than real. There are two broad classes of cell- based therapies: those aimed at restoring structure and function of specific tissues and cells; and those directed towards restoring immunological homeostasis by controlling the damaging effects of inflammatory disease. Stem cells of all types represent the first group and prototypically have been used with the aim of regenerating failing cells. In contrast, immune cells have been suggested as potential modulators of inflammation. However, there is functional overlap in these two applications, with some types of stem cells, such as mesenchymal stem cells, demonstrating a potent immunomodulatory effect. This review summarises recent information on cell based therapies for ocular disease, with special emphasis on ocular inflammatory disease, and explores current uses, potential and limitations.
    Progress in Retinal and Eye Research 03/2013; · 9.44 Impact Factor
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    ABSTRACT: Models of high-risk corneal graft rejection involve neovascularization induced via innate immune responses, e.g., suture-mediated trauma. We describe a model of high-risk corneal graft rejection using corneal graft donor-recipient pairing based on a single-antigen disparity. Donor corneas from transgenic mice on B10.BR (H-2(k) ) background, in which hen-egg lysozyme (HEL) as a membrane-bound antigen (mHEL) was expressed under the major histocompatibility complex (MHC) Class I promoter (KLK-mHEL, H-2(k) ), were transplanted into wild type B10.BR recipient mice. Unmanipulated wild type recipient mice rejected KLK-mHEL grafts (39%) slowly over 50-60 days. Graft rejection incidence was maximized (100%) and tempo accelerated (27 days) by priming with HEL-pulsed syngeneic dendritic cells and less so by increasing T-cell precursor frequency. Rejection also reached maximum levels (100%) and tempo (3-8 days) when mice which had rejected a first graft ('rejectors') were regrafted, and was associated with induction of HEL-specific memory T cells. In contrast, 'acceptors' rejected a second graft at rates and tempo similar to naïve mice. These data reveal the importance of (i) donor MHC antigens as alloantigens for indirect recognition, (ii) alloantigen-specific memory in high-risk graft rejection involving regrafts, and (iii) suggest a role for tissue matching in human corneal graft to avoid sensitization to donor MHC antigens.
    Transplant International 02/2013; · 3.16 Impact Factor
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    ABSTRACT: Microglial cells are the resident macrophages of the central nervous system and participate in both innate and adaptive immune responses but can also lead to exacerbation of neurodegenerative pathologies after viral infections. Microglia in the outer layers of the retina and the subretinal space are thought to be involved in retinal diseases where low-grade chronic inflammation and oxidative stress play a role. This study investigated the effect of systemic infection with murine cytomegalovirus on the distribution and dynamics of retinal microglia cells. Systemic infection with murine cytomegalovirus elicited a significant increase in the number of microglia in the subretinal space and an accumulation of iris macrophages, along with morphological signs of activation. Interferon γ (IFN-γ)-deficient mice failed to induce changes in microglia distribution. Bone marrow chimera experiments confirmed that microglial cells in the subretinal space were not recruited from the circulating monocyte pool, but rather represented an accumulation of resident microglial cells from within the retina. Our results demonstrate that a systemic viral infection can lead to IFN-γ-mediated accumulation of microglia into the outer retinal layers and offer proof of concept that systemic viral infections alter the ocular microenvironment and therefore, may influence the course of diseases such as macular degeneration, diabetic retinopathy, or autoimmune uveitis, where low-grade inflammation is implicated.
    American Journal Of Pathology 01/2013; · 4.60 Impact Factor
  • J V Forrester
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    ABSTRACT: Inflammation, in the pathogenesis of many diseases previously thought to be strictly genetic, degenerative, metabolic, or endocrinologic in aetiology, has gradually entered the framework of a general mechanism of disease. This is exemplified by conditions such as Parkinson's disease, Alzheimer's disease, atherosclerosis, diabetes, and the more recently described Metabolic Syndrome. Chronic inflammatory processes have a significant, if not primary role, in ophthalmic diseases, particularly in retinal degenerative diseases. However, inflammation itself is not easy to define, and some aspects of inflammation may be beneficial, in a process described as 'para-inflammation' by Medhzitov. In contrast, the damaging effects of inflammation, mediated by pro-inflammatory macrophages through activation of the intracellular protein-signalling complexes, termed inflammasomes, are well recognised and are important therapeutic targets. In this review, the range of inflammatory processes in the eye is evaluated in the context of how these processes impact upon retinal degenerative disease, particularly diabetic retinopathy and age-related macular degeneration.Eye advance online publication, 4 January 2013; doi:10.1038/eye.2012.265.
    Eye (London, England) 01/2013; · 1.97 Impact Factor
  • John V Forrester, Izabela P Klaska, Tian Yu, Lucia Kuffova
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    ABSTRACT: Uveitis is underappreciated as a sight-threatening cause of blindness. There are two broad causative classes of uveitis: infectious and non-infectious. Non-infectious uveitis is considered a prototypical autoimmune disorder based mainly on data from experimental models in the mouse. Several different experimental models exist that reflect the different types of uveitis in man (anterior, intermediate, and posterior uveitis). These models have demonstrated that uveitis is predominantly a Th1/Th17 mediated disease, although innate immune cells play a significant role both in induction of disease and in tissue damage. Most experimental models of uveitis rely on activation of the innate immune system by use of adjuvants that activate a range of pathogen recognition receptors (PRRs). This begs the question of the underlying role of initial and/or persistent infection, including latent infection, in immune-mediated uveitis in which active infection cannot be demonstrated. This further raises the possibility of pathogenic mechanisms such as antigenic cross-reactivity and molecular mimicry. Alternatively, residual/latent antigen from infectious agents may act as "endogenous" adjuvants for induction of immune reactions to damaged/altered self antigen, suggesting a commonality in pathogenesis for both infectious and non-infectious uveitis in man.
    International Reviews Of Immunology 01/2013; 32(1):76-96. · 5.73 Impact Factor
  • John V Forrester
    Investigative ophthalmology & visual science 01/2013; 54(3):2258-65. · 3.43 Impact Factor
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    ABSTRACT: Idiopathic intermediate uveitis (IIU) is a potentially sight-threatening inflammatory disorder with well-defined anatomic diagnostic criteria. It is often associated with multiple sclerosis, and both conditions are linked to HLA-DRB1*15. Previously, we have shown that non-infectious uveitis (NIU) is associated with interleukin 10 (IL10) polymorphisms, IL10-2849A (rs6703630), IL10+434T (rs2222202), and IL10+504G (rs3024490), while a LTA+252AA/TNFA-238GG haplotype (rs909253/rs361525) is protective. In this study, we determined whether patients with IIU have a similar genetic profile as patients with NIU or multiple sclerosis. Twelve polymorphisms were genotyped, spanning the tumor necrosis factor (TNF) and IL10 genomic regions, in 44 patients with IIU and 92 population controls from the UK and the Republic of Ireland. IIU was strongly associated with the TNFA-308A and TNFA-238A polymorphisms. We found the combination of TNFA-308 and -238 loci was more strongly associated with IIU than any other loci across the major histocompatibility complex, including HLA-DRB1. TNF polymorphisms, associated with increased TNF production, are highly associated with IIU. These results offer the potential to ascribe therapeutic response and risk (i.e., the influence of HLA-DRB1*15 status and TNFR1 polymorphism) to anti-TNF therapy in IIU.
    Molecular vision 01/2013; 19:184-95. · 1.99 Impact Factor
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    ABSTRACT: Previous studies have shown that CCL2/CX3CR1 deficient mice on C57BL/6N background (with rd8 mutation) have an early onset (6 weeks) of spontaneous retinal degeneration. In this study, we generated CCL2(-/-)CX3CR1(GFP/GFP) mice on the C57BL/6J background. Retinal degeneration was not detected in CCL2(-/-)CX3CR1(GFP/GFP) mice younger than 6 months. Patches of whitish/yellowish fundus lesions were observed in 17∼60% of 12-month, and 30∼100% of 18-month CCL2(-/-)CX3CR1(GFP/GFP) mice. Fluorescein angiography revealed no choroidal neovascularisation in these mice. Patches of retinal pigment epithelium (RPE) and photoreceptor damage were detected in 30% and 50% of 12- and 18-month CCL2(-/-)CX3CR1(GFP/GFP) mice respectively, but not in wild-type mice. All CCL2(-/-)CX3CR1(GFP/GFP) mice exposed to extra-light (∼800lux, 6 h/day, 6 months) developed patches of retinal atrophy, and only 20-25% of WT mice which underwent the same light treatment developed atrophic lesions. In addition, synaptophysin expression was detected in the outer nucler layer (ONL) of area related to photoreceptor loss in CCL2(-/-)CX3CR1(GFP/GFP) mice. Markedly increased rhodopsin but reduced cone arrestin expression was observed in retinal outer layers in aged CCL2(-/-)CX3CR1(GFP/GFP) mice. GABA expression was reduced in the inner retina of aged CCL2(-/-)CX3CR1(GFP/GFP) mice. Significantly increased Müller glial and microglial activation was observed in CCL2(-/-)CX3CR1(GFP/GFP) mice compared to age-matched WT mice. Macrophages from CCL2(-/-)CX3CR1(GFP/GFP) mice were less phagocytic, but expressed higher levels of iNOS, IL-1β, IL-12 and TNF-α under hypoxia conditions. Our results suggest that the deletions of CCL2 and CX3CR1 predispose mice to age- and light-mediated retinal damage. The CCL2/CX3CR1 deficient mouse may thus serve as a model for age-related atrophic degeneration of the RPE, including the dry type of macular degeneration, geographic atrophy.
    PLoS ONE 01/2013; 8(4):e61381. · 3.53 Impact Factor
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    Mei Chen, Elizabeth Muckersie, Heping Xu, John V Forrester

Publication Stats

8k Citations
1,203.72 Total Impact Points

Institutions

  • 1992–2014
    • University of Western Australia
      • • Center for Experimental Immunology
      • • School of Anatomy, Physiology and Human Biology
      Perth City, Western Australia, Australia
  • 1987–2014
    • University of Aberdeen
      • • Institute of Medical Sciences
      • • Division of Applied Medicine
      • • School of Engineering
      Aberdeen, Scotland, United Kingdom
  • 2013
    • Ottawa Hospital Research Institute
      Ottawa, Ontario, Canada
  • 2010–2013
    • Queen's University Belfast
      • Centre for Vision and Vascular Science
      Belfast, NIR, United Kingdom
  • 2003–2012
    • University of Bristol
      • School of Clinical Sciences
      Bristol, ENG, United Kingdom
    • The Bracton Centre, Oxleas NHS Trust
      Дартфорде, England, United Kingdom
  • 2011
    • Monash University (Australia)
      • School of Biomedical Sciences
      Melbourne, Victoria, Australia
  • 2008
    • Charité Universitätsmedizin Berlin
      • Department of Ophthalmology
      Berlín, Berlin, Germany
    • University of Ottawa
      • Department of Cellular and Molecular Medicine
      Ottawa, Ontario, Canada
  • 2007
    • Royal Perth Hospital
      Perth City, Western Australia, Australia
    • University of Coimbra
      • Faculdade de Medicina
      Coimbra, Distrito de Coimbra, Portugal
  • 2006
    • University of Oxford
      • Nuffield Department of Clinical Medicine
      Oxford, ENG, United Kingdom
  • 2005
    • Academy of Sciences of the Czech Republic
      • Institute of Molecular Genetics
      Praha, Praha, Czech Republic
  • 1992–2003
    • Moorfields Eye Hospital NHS Foundation Trust
      Londinium, England, United Kingdom
  • 2000
    • University of Birmingham
      • School of Mathematics
      Birmingham, ENG, United Kingdom
  • 1993
    • Wills Eye Institute
      Philadelphia, Pennsylvania, United States
  • 1983–1987
    • University of Glasgow
      Glasgow, Scotland, United Kingdom