Andrew Leask

Western University, London, Ontario, Canada

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Publications (197)645.62 Total impact

  • PLoS ONE 04/2015; 10(4):e0123689. DOI:10.1371/journal.pone.0123689 · 3.53 Impact Factor
  • Andrew Leask
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    ABSTRACT: Chronic wounds, especially on the feet, are a clinical feature resulting from diabetes and often result in limb amputation. Identification of strategies that promote closure of chronic wounds are essential. In a study authored by Henshaw et al. (J Diabetes Res. 2015;2015:236238), CCN2/CTGF was able to accelerated closure of wounds in diabetic rats. Moreover, in humans, the ability of wounds in diabetic patients to heal correlated with CCN2 expression. Thus CCN2 might, in the future, be used to promote healing of chronic wounds.Diabetic foot ulcers are a significant cause of morbidity and are a substantial financial burden. Approximately 25 % of diabetics have foot ulcers, and these account for up to 70 % of non traumatic lower limb amputations (Most and Sinnock 1983). About 6.5 million people in the USA suffer from chronic wounds, costing ~ $25 billion dollars (Sen et al. 2009). Developing novel methods of promoting closure of chronic diabetic wounds is therefore of paramount importanc ...
    Journal of Cell Communication and Signaling 04/2015; DOI:10.1007/s12079-015-0292-8
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    ABSTRACT: The matricellular secreted protein, connective tissue growth factor (CTGF), is upregulated in response to cardiac injury or with transforming growth factor β (TGFβ) stimulation, where it has been suggested to function as a fibrotic effector. Here we generated transgenic mice with inducible cardiac-specific CTGF overexpression, mice with cardiac-specific expression of an activated TGFβ mutant protein, mice with cardiac-specific deletion of Ctgf, and mice in which Ctgf was also deleted from fibroblasts in the heart. Remarkably, neither gain nor loss of CTGF in the heart affected cardiac pathology and propensity toward early lethality due to TGFβ over activation in the heart. Also, neither heart-specific Ctgf deletion nor CTGF overexpression altered cardiac remodeling and function with aging or after multiple acute stress stimuli. Cardiac fibrosis was also unchanged by modulation of CTGF levels in the heart with aging, pressure overload, agonist infusion or TGFβ overexpression. However, CTGF did mildly alter the overall cardiac response to TGFβ when pressure overload stimulation was applied. CTGF has been proposed to function as a critical TGFβ effector in underlying tissue remodeling and fibrosis throughout the body, although our results suggest that CTGF is of minimal importance and is an unlikely therapeutic vantage point for the heart. Copyright © 2015, American Society for Microbiology. All Rights Reserved.
    Molecular and Cellular Biology 04/2015; DOI:10.1128/MCB.00199-15 · 5.04 Impact Factor
  • Andrew Leask
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    ABSTRACT: Fibrotic diseases are a significant global burden for which there are limited treatment options. The effector cells of fibrosis are activated fibroblasts called myofibroblasts, a highly contractile cell type characterized by the appearance of α-smooth muscle actin stress fibers. The underlying mechanism behind myofibroblast differentiation and persistence has been under much investigation and is known to involve a complex signaling network involving transforming growth factor-β, endothelin-1, angiotensin II, CCN2 (connective tissue growth factor), and platelet-derived growth factor. This review addresses the contribution of these signaling molecules to cardiac fibrosis. © 2015 American Heart Association, Inc.
    Circulation Research 03/2015; 116(7):1269-1276. DOI:10.1161/CIRCRESAHA.116.305381 · 11.09 Impact Factor
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    ABSTRACT: Non-healing skin wounds remain a significant clinical burden, and in recent years, the regulatory role of matricellular proteins in skin healing has received significant attention. Periostin and CCN2 are both upregulated at day 3 post-wounding in murine skin, where they regulate aspects of the proliferative phase of repair including mesenchymal cell infiltration and myofibroblast differentiation. In this study, we examined 1) the wound phenotype and expression patterns of periostin and CCN2 in non-healing skin wounds in humans and 2) the regulation of their expression in wound fibroblasts by tumour necrosis factor α (TNFα) and transforming growth factor-β1 (TGF-β1). Chronic skin wounds had a pro-inflammatory phenotype, characterized by macrophage infiltration, TNFα immunoreactivity, and neutrophil infiltration. Periostin, but not CCN2, was significantly suppressed in non-healing wound edge tissue at the mRNA and protein level compared with non-involved skin. In vitro, human wound edge fibroblasts populations were still able to proliferate and contract collagen gels. Compared to cells from non-involved skin, periostin and α-SMA mRNA levels increased significantly in the presence of TGF-β1 in wound cells and were significantly decreased by TNFα, but not those of Col1A2 or CCN2. In the presence of both TGF-β1 and TNFα, periostin and α-SMA mRNA levels were significantly reduced compared to TGF-β1 treated wound cells. Effects of TGF-β1 and TNFα on gene expression were also more pronounced in wound edge cells compared to non-involved fibroblasts. We conclude that variations in the expression of periostin and CCN2, is related to an inflammatory microenvironment and the presence of TNFα in human chronic wounds. Copyright © 2015. Published by Elsevier B.V.
    Matrix biology: journal of the International Society for Matrix Biology 03/2015; 36. DOI:10.1016/j.matbio.2015.03.003 · 3.65 Impact Factor
  • Andrew Leask
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    ABSTRACT: Fibrotic diseases are a significant cause of mortality. It is being increasingly appreciated that the cellular microenvironment plays a key role in promoting pathological fibrosis. A previous Bits and Bytes described an elegant series of experiments published by Bruce Riser and colleagues (Am J Pathol. 2009: 174:1725-34) that showed that CCN3 (nov) antagonizes the fibrogenic effects of CCN2.and hence could represent a novel anti-fibrotic therapy. They have continued their excellent work and have recently used the ob/ob mouse as a model of obesity and diabetic nephropathy to show that CCN3 could block the induction of profibrotic gene expression, fibrosis and loss of kidney function (Am J Pathol. 2014;184:2908-21). Also, reversal of fibrosis was observed. Thus this paper provides strong evidence that CCN3 may be used as a novel therapy to treat diabetes caused by obesity.
    Journal of Cell Communication and Signaling 02/2015; 9(1). DOI:10.1007/s12079-015-0281-y
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    ABSTRACT: Elevated adhesive signaling promotes fibrosis. Protein phosphatase and tensin homologue (PTEN) dephosphorylates focal adhesion kinase and suppresses the activation of Akt and hence suppresses adhesive signaling. Loss of PTEN expression is associated with lung fibrosis, but whether PTEN expression by type I collagen-expressing cells controls lung fibrosis is unclear. Here, we use mice expressing tamoxifen-dependent cre recombinase expressed under the control of a COL1A2 promoter/enhancer and mice harboring floxed-PTEN and/or floxed-CCN2 alleles to assess whether loss of PTEN expression by type I collagen producing cells results in lung fibrosis in a CCN2-dependent fashion. In vivo, loss of PTEN expression resulted in the overexpression of both collagen type I and the pro-adhesive matricellular protein connective tissue growth factor (CTGF/CCN2). However, α−smooth muscle actin expression was unaffected. Loss of CCN2 expression by lung fibroblasts rescues this phenotype; i.e.., mice deficient in both PTEN and CCN2 in collagen type I-expressing cells do not develop significant collagen deposition in the lung. PTEN expression by collagen type I-expressing cells controls collagen deposition; therapeutic strategies blocking CCN2 may be of benefit in blocking excessive collagen deposition in fibrosis.
    Matrix Biology 01/2015; 9. DOI:10.1016/j.matbio.2015.01.017 · 3.65 Impact Factor
  • 01/2015; DOI:10.2147/RRBC.S57407
  • Matthew Tsang, Andrew Leask
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    ABSTRACT: Connective tissue growth factor (CTGF/CCN2), a member of the CCN family of matricellular proteins is upregulated in both fibrosis as well as tissue repair. Recently, we showed that, in mice, CCN2 expression by fibroblasts was required for dermal fibrogenesis, but not for cutaneous tissue repair. Lineage tracing analysis linked the ability of CCN2 to promote fibrosis to the requirement for CCN2 to recruit cells expressing the progenitor cell marker Sox2 to fibrotic connective tissue and for differentiating these cells into myofibroblasts. Herein, we show that although loss of CCN2 expression by Sox2-expressing cells does not impair cutaneous tissue repair, CCN2 was required for recruitment of cells derived from Sox2-expressing cells to the wound area. Collectively, these results are consistent with the notion that neither CCN2 nor Sox2-expressing progenitor cells are essential for cutaneous tissue repair and that CCN2 represents a specific anti-fibrotic target.
    Journal of Cell Communication and Signaling 10/2014; DOI:10.1007/s12079-014-0245-7
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    ABSTRACT: There is a critical need for techniques that directly monitor protein synthesis within cells isolated from normal and diseased tissue. Fibrotic disease, for which there is no drug treatment, is characterized by the overexpression of collagens. Here, we use a bioinformatics approach to identify a pair of glycine and proline isoacceptor tRNAs as being specific for the decoding of collagen mRNAs, leading to development of a FRET-based approach, dicodon monitoring of protein synthesis (DiCoMPS), that directly monitors the synthesis of collagen. DiCoMPS aimed at detecting collagen synthesis will be helpful in identifying novel anti-fibrotic compounds in cells derived from patients with fibrosis of any etiology, and, suitably adapted, should be widely applicable in monitoring the synthesis of other proteins in cells. J. Cell. Physiol. © 2014 Wiley Periodicals, Inc.
    Journal of Cellular Physiology 09/2014; 229(9). DOI:10.1002/jcp.24630 · 3.87 Impact Factor
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    ABSTRACT: Connective tissue growth factor (CTGF) is a matricellular protein that mediates cell-matrix interaction through various subtypes of integrin receptors. This study investigated the role of CTGF and integrin αvβ6 in hepatic progenitor/oval cell activation, which often occurs in the form of ductular reactions (DRs) when hepatocyte proliferation is inhibited during severe liver injury. CTGF and integrin αvβ6 proteins were highly expressed in DRs of human cirrhotic livers and cholangiocarcinoma. Confocal microscopy analysis of livers from Ctgf promoter driven GFP reporter mice suggested that oval cells and cholangiocytes were the main sources of CTGF and integrin αvβ6 during liver injury induced by 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC). Deletion of exon 4 of the Ctgf gene using tamoxifen inducible Cre-loxP system down-regulated integrin αvβ6 in DDC damaged livers of knockout mice. Ctgf deficiency or inhibition of integrin αvβ6 by administrating the neutralizing antibody 6.3G9 (10 mg/kg body weight) caused low levels of EpCAM and CK19 mRNAs. Also, there were smaller oval cell areas, fewer proliferating ductular epithelial cells, and lower cholestasis serum markers within two weeks after DDC treatment. Associated fibrosis was attenuated as indicated by reduced expression of fibrosis-related genes, smaller areas of α smooth muscle actin staining and low collagen production based on hydroxyproline content and the Sirius red staining. Finally, integrin αvβ6 could bind to CTGF mediating oval cell adhesion to CTGF and fibronection substrata and promoting transforming growth factor (TGF)-β1 activation in vitro. Conclusions: CTGF and integrin αvβ6 regulate oval cell activation and fibrosis, probably through interacting with their common matrix and signal partners, fibronectin and TGF-β1. CTGF and integrin αvβ6 are potential therapeutic targets to control DRs and fibrosis in related liver disease. (Hepatology 2014)
    Hepatology 09/2014; 61(2). DOI:10.1002/hep.27425 · 11.19 Impact Factor
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    ABSTRACT: The so-called "matricellular" proteins have recently emerged as important regulators of cell-extracellular matrix (ECM) interactions. These proteins modulate a variety of cell functions through a range of interactions with cell-surface receptors, hormones, proteases and structural components of the ECM. As such, matricellular proteins are crucial regulators of cell phenotype, and consequently tissue function. The distinct cell types and microenvironments that together form the IVD provide an excellent paradigm to study how matricellular proteins mediate communication within and between adjacent tissue types. In recent years, the role of several matricellular proteins in the intervertebral disc has been explored in vivo using mutant mouse models in which the expression of target matricellular proteins was deleted from either one or all compartments of the intervertebral disc. The current review outlines what is presently known about the roles of the matricellular proteins belonging to the CCN family, SPARC (Secreted Protein, Acidic, and Rich in Cysteine), and thrombospondin (TSP) 2 in regulating intervertebral disc cell-ECM interactions, ECM synthesis and disc tissue homeostasis using genetically modified mouse models. Furthermore, we provide a brief overview of recent preliminary studies of other matricellular proteins including, periostin (POSTN) and tenascin (TN). Each specific tissue type of the IVD contains a different matricellular protein signature, which varies based on the specific stage of development, maturity or disease. A growing body of direct genetic evidence links IVD development, maintenance and repair to the coordinate interaction of matricellular proteins within their respective niches and suggest that several of these signalling modulators hold promise in the development of diagnostics and/or therapeutics targeting intervertebral disc aging and/or degeneration.
    Matrix biology: journal of the International Society for Matrix Biology 05/2014; 37. DOI:10.1016/j.matbio.2014.05.005 · 3.65 Impact Factor
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    ABSTRACT: Purpose: This study aimed to elucidate the role of connective tissue growth factor (CTGF) in normal eyes and wounded corneas of mice and rabbits. Conditional knockout mice were utilized to determine the role of CTGF in corneal healing. Methods: CTGF expression was determined using transgenic mice carrying CTGF promoter-driven-eGFP, quantitative RT-PCR, and immunohistochemistry. Mice that carried two floxed CTGF alleles and a Cre/ERT2 transgene under the control of human ubiquitin C (ubc) promoter were utilized to conditionally delete CTGF gene in a tamoxifen-inducible manner. Phototherapeutic keratectomy (PTK) was used to generate an acute corneal wound and corneal re-epithelialization was assessed by fluorescein staining. Results: CTGF expression was found in multiple ocular tissues with relatively high levels in the corneal endothelium, lens subcapsular epithelium, and in the vasculature of the iris and retina. Wounded corneas responded with an immediate up-regulation of CTGF in the epithelium at the wound margin and a sustained CTGF induction during re-epithelialization. At the onset of haze formation, CTGF protein becomes more focused in the basal epithelium. Deletion of the CTGF gene caused a 40% reduction (P<0.01) in the cornea re-epithelialization rate in knockout mice compared with wild type mice. Conclusions: CTGF is expressed in the naïve cornea, lens, iris and retina, and is expressed immediately after epithelial injury. Loss of CTGF impairs efficient re-epithelialization of corneal wounds.
    Investigative ophthalmology & visual science 03/2014; 55(4). DOI:10.1167/iovs.13-12735 · 3.66 Impact Factor
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    ABSTRACT: The origin of the cells that contribute to skin fibrosis is unclear. Herein, we assess the contribution of sox2-expressing skin progenitor cells to bleomycin-induced skin scleroderma. We subject wild-type mice and mice in which CCN2 is deleted in sox2-expressing cells to bleomycin-induced skin scleroderma. We also conduct lineage tracing analysis to assess whether cells expressing sox2 are recruited to fibrotic lesions in response to bleomycin-induced scleroderma. In response to bleomycin, sox2-positive/α-smooth muscle actin-positive cells are recruited to fibrotic tissue. Conditional CCN2 knockout mice in which CCN2 is deleted in sox2-expressing cells exhibit resistance to bleomycin-induced skin fibrosis. Collectively, these results indicate that CCN2 is required for the recruitment of progenitor cells and that CCN2-expressing progenitor cells are essential for bleomycin-induced skin fibrosis. Lineage tracing using mice in which a tamoxifen-dependent cre recombinase is expressed under the control of the sox2 promoter confirm that progenitor cells are recruited to the fibrotic lesion in response to bleomycin, but not in CCN2-knockout mice. CCN2 is required for the ability of serum to induce α-smooth muscle actin expression in skin progenitor cells. Sox2-positive skin progenitor cells are required for bleomycin-induced skin fibrosis and CCN2 is required for their recruitment to the fibrotic lesion. Targeting stem cell recruitment or CCN2 may therefore represent useful targets in combating fibrotic skin disease. © 2013 American College of Rheumatology.
    Arthritis & Rheumatology 03/2014; 66(3). DOI:10.1002/art.38276 · 7.87 Impact Factor
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    ABSTRACT: The potent profibrotic cytokine TGFβ induces connective tissue growth factor (CCN2/CTGF) is induced in fibroblasts in a fashion sensitive to SB-431542, a specific pharmacological inhibitor of TGFβ type I receptor (ALK5). In several cell types, TGFβ induces CCN1 but suppresses CCN3, which opposes CCN1/CCN2 activities. However, whether SB-431542 alters TGFβ-induced CCN1 or CCN3 in human foreskin fibroblasts in unclear. Here we show that TGFβ induces CCN1 but suppresses CCN3 expression in human foreskin fibroblasts in a SB-431542-sensitive fashion. These results emphasize that CCN1/CCN2 and CCN3 are reciprocally regulated and support the notion that blocking ALK5 or addition of CCN3 may be useful anti-fibrotic approaches.
    Journal of Cell Communication and Signaling 02/2014; 8(1). DOI:10.1007/s12079-014-0229-7
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    Fen Guo, David E Carter, Andrew Leask
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    ABSTRACT: Scarring, which occurs in essentially all adult tissue, is characterized by the excessive production and remodeling of extracellular matrix by α-smooth muscle actin (SMA)-expressing myofibroblasts located within connective tissue. Excessive scarring can cause organ failure and death. Oral gingivae do not scar. Compared to dermal fibroblasts, gingival fibroblasts do not respond to transforming growth factor (TGFβ) by inducing α-SMA expression, due to the reduced expression and activity of focal adhesion kinase (FAK) by this cell type. Herein, we show that, compared with dermal fibroblasts, gingival fibroblasts show reduced expression of miR-218. Introduction of pre-miR-218 into gingival fibroblasts elevates FAK expression and, via a FAK/src-dependent mechanism, results in the ability of TGFβ to induce α-SMA. The deubiquitinase cezanne is a direct target of miR-218 and has increased expression in gingival fibroblasts compared with dermal fibroblasts. Knockdown of cezanne in gingival fibroblasts increases FAK expression and causes TGFβ to induce α-SMA. These results suggest that miR-218 regulates the ability of TGFβ to induce myofibroblast differentiation in fibroblasts via cezanne/FAK.
    Molecular biology of the cell 02/2014; 25(7). DOI:10.1091/mbc.E13-08-0451 · 5.98 Impact Factor
  • Andrew Leask, James Hutchenreuther
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    ABSTRACT: Cell-mediated activation of latent TGF-β1 is intimately involved with tissue repair and fibrosis in all organs. Previously, it was shown that the integrin β1 subunit was required for activation of latent TGF-β1 and skin fibrosis. A recent study by Henderson and colleagues (Nature Medicine 19,1617-1624, 2013) used three different in vivo models of fibrosis to show that integrin αv subunit was required for fibrogenesis. Through a process of elimination, the authors conclude that in vivo, the little-studied αvβ1 could be the major integrin responsible for TGF-β activation by myofibroblasts. Thus targeting this integrin might be a useful therapy for fibrosis.
    Journal of Cell Communication and Signaling 01/2014; DOI:10.1007/s12079-014-0221-2
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    ABSTRACT: The so-called “matricellular” proteins have recently emerged as important regulators of cell-extracellular matrix (ECM) interactions. These proteins modulate a variety of cell functions through a range of interactions with cell-surface receptors, hormones, proteases and structural components of the ECM. As such, matricellular proteins are crucial regulators of cell phenotype, and consequently tissue function. The distinct cell types and microenvironments that together form the IVD provide an excellent paradigm to study how matricellular proteins mediate communication within and between adjacent tissue types. In recent years, the role of several matricellular proteins in the intervertebral disc has been explored in vivo using mutant mouse models in which the expression of target matricellular proteins was deleted from either one or all compartments of the intervertebral disc. The current review outlines what is presently known about the roles of the matricellular proteins belonging to the CCN family, SPARC (Secreted Protein, Acidic, and Rich in Cysteine), and thrombospondin (TSP) 2 in regulating intervertebral disc cell-ECM interactions, ECM synthesis and disc tissue homeostasis using genetically modified mouse models. Furthermore, we provide a brief overview of recent preliminary studies of other matricellular proteins including, periostin (POSTN) and tenascin (TN). Each specific tissue type of the IVD contains a different matricellular protein signature, which varies based on the specific stage of development, maturity or disease. A growing body of direct genetic evidence links IVD development, maintenance and repair to the coordinate interaction of matricellular proteins within their respective niches and suggest that several of these signalling modulators hold promise in the development of diagnostics and/or therapeutics targeting intervertebral disc aging and/or degeneration.
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    ABSTRACT: The CCN family of matricellular proteins, which includes CCN2 and CCN1, is believed to have a major in vivo role in controlling tissue morphogenesis and repair. In adult skin, the proadhesive matricellular protein connective tissue growth factor (CTGF/CCN2) is specifically up-regulated in fibrosis and wound healing. In mice, CCN2 is required for dermal fibrogenesis, but whether CCN2 is required for cutaneous tissue repair is unknown. To address this question, in this report we subjected adult mice bearing a fibroblast-specific deletion of CCN2 to the dermal punch model of cutaneous tissue repair. Loss of CCN2 did not appreciably affect the kinetics of tissue repair, collagen content, or the number of α-smooth muscle actin-positive cells. CCN1 (cyr61), which has in vitro effect similar to CCN2, is also induced in cutaneous tissue repair. Fibroblast-specific CCN1/CCN2 double knockout mice were also generated; loss of both CCN1 and CCN2 together did not appreciably affect cutaneous tissue repair. However, loss of CCN2 resulted in impaired recruitment of NG2-positive pericyte-like cells to the wound area. Collectively, these results indicate that neither CCN2 nor CCN1 is essential for cutaneous tissue repair; CCN2 appears to be required for recruitment of pericyte-like cells and may represent a specific antifibrotic target.
    Wound Repair and Regeneration 01/2014; 22(1):119-24. DOI:10.1111/wrr.12131 · 2.77 Impact Factor
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    ABSTRACT: In this report, chairs of the 7th International Workshop on the CCN family of Genes, review the progress made in understanding the biological functions of CCN proteins (CCN1, CCN2, CCN3, CCN4, CCN5 and CCN6) with a particular focus on their implications in various pathological conditions, including cancer, fibrosis, diabetes, and cardiovascular diseases.
    Journal of Cell Communication and Signaling 01/2014; 8(1). DOI:10.1007/s12079-014-0227-9

Publication Stats

7k Citations
645.62 Total Impact Points

Institutions

  • 2012–2015
    • Western University
      London, Ontario, Canada
  • 2006–2015
    • The University of Western Ontario
      • • Department of Physiology and Pharmacology
      • • Schulich School of Medicine and Dentistry
      London, Ontario, Canada
    • University of California, Los Angeles
      Los Ángeles, California, United States
  • 2003–2011
    • University College London
      • • Centre for Rheumatology and Connective Tissue Disease
      • • Centre for Rheumatology
      Londinium, England, United Kingdom
  • 2004–2006
    • Imperial College London
      Londinium, England, United Kingdom
  • 2005
    • University of Westminster
      Londinium, England, United Kingdom
  • 2001
    • FibroGen
      San Francisco, California, United States