Professor Daniel Aeschlimann
Director of Research, Professor of Biological Sciences
Structure and function of proteins in the extracellular matrix, mechanisms for the assembly of supramolecular structures and role of extracellular matrix in guiding cellular responses. Molecular aspects of connective tissue in development and ageing. The role of protein cross-linking by transglutaminases in these processes. Application of knowledge to understanding and treatment of human diseases, particularly diseases of the musculoskeletal system. Development of smart materials for cell based therapy to promote wound healing and tissue regeneration.
Action Medical Research "Role of fibroblast extracellular matrix in regulation of epithelial cells in health and disease"
Fibroblasts deposit a highly organized and tissue-specific extracellular matrix and hence provide a local microenvironment that controls repair processes. For example, fibroblasts have an instructive function in regulation of an overlying epithelium and defects in epithelial regeneration result as a consequence of altered matrix deposition or remodelling. Tissue transglutaminase (TG2)-deficient mice display aberrant wound healing responses and we have shown that TG2 (a multifunctional protein associated with the early phase of wound healing) contributes to fibroblast-mediated extracellular matrix remodeling in several ways (Stephens et al., 2004. J. Cell Sci. 117, 3389-3403). In this project, we will use an in-house developed co-culture model of fibroblasts and epithelial cells that mimics the re-epithelialisation process observed in skin wound healing to investigate whether TG2-mediated extracellular matrix remodelling plays a role in the crosstalk between the two cell types.
BRET / Ryder Briggs Trust $acirc; The role of transglutaminases in immune mediated neurological diseases:
Gluten sensitivity typically presents as celiac disease, a chronic autoimmune-mediated small intestinal disorder. In susceptible individuals with specific human lymphocyte antigens, consumption of gluten triggers a CD4+ T cell response to gliadin as well as a B cell response to gliadin and self antigens. Tissue transglutaminase (TG2) is the autoantigen recognized in the endomysium of the gut by sera from patients with celiac disease. However, gluten sensitivity can manifest as a spectrum of clinical conditions. For example, neurological disorders occur with a frequency of up to 10% among celiac disease patients, but neurological dysfunction can also be the sole presenting feature of gluten sensitivity. Development of autoimmunity directed towards different members of the transglutaminase family could offer an explanation for the diversity in manifestations of gluten sensitivity. We have identified a novel neuronal transglutaminase isozyme (Grenard et al., 2001. J. Biol. Chem. 276, 33066-33078) and this project investigates whether this enzyme is the target of the immune response in patients with neurological dysfunction.
NATO; Modelling of hydrodynamic stresses in hydrogel environment that supports vasculogenesis$acirc; :
A major challenge for cell transplantation and in vitro engineering of larger tissue equivalents, like organs, is the lack of a functional vasculature to deliver sufficient nutrition and oxygenation. A cascade of morphogenetic processes is required for blood vessel formation which besides the now well characterized signalling events (growth factors and chemokines) also involves gradients of small molecules and mechanotransduction through the extracellular environment. This project aims to provide an understanding of the correlation between interstitial fluid flow parameters and angiogenic responses of endothelial cells seeded into a 3-dimensional hydrogel environment (Bulpitt and Aeschlimann, 1999.J. Biomed. Mater. Res. 47, 152-169) and based on this knowledge, to develop technology that allows for the establishment of a simple vasculature for support of engineered organ equivalents.
MSc (Diploma in Biology II: Biochemistry, Biophysical Chemistry, Cell Biology and Molecular Genetics), Biocenter, University of Basel, Basel, Switzerland.
PhD in Biochemistry (rated Summa Cum Laude), University of Basel, Basel, Switzerland.
Postdoctoral fellow in the group of Dr. Mats Paulsson, M. E. MÃ ller-Institute for Biomechanics, University of Bern, Bern, Switzerland.
Fellowship from the European Molecular Biology Organization, Heidelberg, Germany to work with Dr. Deane F. Mosher, Department of Medicine, University of Wisconsin, Madison, USA.
Senior Scientist and Principal Investigator, Division of Orthopedic Surgery, University of Wisconsin, Madison, USA (received Fellowship for Advanced Researchers from Swiss National Science Foundation in 1996/1997)
Lecturer in Biochemistry, Cardiff University, Cardiff, U.K.
Professor of Biological Sciences, School of Dentistry, Cardiff University, Cardiff, U.K.
Reviewer for Journals:
Member of Editorial Board of The Journal of Biological Chemistry (2000-2002)
Ad hoc Reviewer for Journals:
Biochemistry, Biomaterials, Cancer Research, Cell Death and Differentiation, European Journal of Biochemistry, European Journal of Cell Biology, Experimental Cell Research, FEBS Lett., Human Molecular Genetics, Journal of Biological Chemistry, Journal of Bone and Mineral Research, Journal of Cell Science, Journal of Clinical Investigation, Journal of Investigative Dermatology, Journal of Neurochemistry, Journal of Orthopedic Research, Matrix Biology, Nature Cell Biology, Neurochemistry International, Osteoarthritis and Cartilage
Reviewer for Funding Bodies:
Action Medical Research, Arthritis Research Campaign, BBSRC, National Kidney Research Fund, Wellcome Trust and National University of Singapore, Singapore
Isopeptidase assay for analysis of transglutaminase activity
Assay to perform kinetic measurements of transglutaminase activity in a high throughput format for the analysis of regulators/inhibitors of catalysis. This document is an extended version of the BMG Labtech Application Note 234, which contains additional data on reaction conditions and a detailed discussion of catalysis.
Influential Research Articles
Hadjivassiliou, M., Aeschlimann, P., Strigun, A., Sanders, D., Woodroofe, N., and Aeschlimann, D. (2008). Autoantibodies in gluten ataxia recognize a novel neuronal transglutaminase. Ann. Neurol. 64, 332-343. Citations: >100
Szondy, Z., Sarang, Z., Molnar, P., Nemeth, T., Piacentini, M., Mastroberardino, P.G., Falasca, L., Aeschlimann, D., Kovacs, J., Kiss, I., Szegezdi, E., Lakos, G., Rajnavolgyi, E., Birckbichler, P.J., Melino, G.,and Fesus, L. (2003). Transglutaminase 2-/- mice reveal a phagocytosis-associated crosstalk between macrophages and apoptotic cells. Proc. Natl. Acad. Sci. USA 100, 7812-7817. Citations: >160
Grenard, P., Bates, M.K, and Aeschlimann, D. (2001). Evolution of transglutaminase genes: Identification of a gene cluster on human chromosome 15q15. Structure of the genes encoding transglutaminase X and a novel gene family member, transglutaminase Z. J. Biol. Chem. 276, 33066-33078. Citations: >140
Bulpitt, P., and Aeschlimann, D. (1999). New strategy for chemical modification of hyaluronic acid: Preparation of functionalized derivatives and their use in the formation of novel biocompatible hydrogels. J. Biomed. Mater. Res. 47, 152-169. Citations: >290
Gaudry, C.A., Verderio, E., Aeschlimann, D., Cox, A., Smith, C., and Griffin, M. (1999). Cell surface localization of tissue transglutaminase is dependent on a fibronectin binding site in its N-terminal b-sandwich domain. J. Biol. Chem. 274, 30707-30714. Citations: >100
Aeschlimann, D., Kaupp, O., and Paulsson, M. (1995). Transglutaminase-catalyzed matrix cross-linking in differentiating cartilage: Identification of osteonectin as a major glutaminyl substrate. J. Cell Biol.129, 881-892. Citations: >160
Aeschlimann, D., Wetterwald, A., Fleisch, H., and Paulsson, M. (1993). Expression of tissue transglutaminase in skeletal tissues correlates with events of terminal differentiation of chondrocytes. J. Cell Biol. 120, 1461-1470. Citations: >150
Hedbom, E., Antonsson, P., Hjerpe, A., Aeschlimann, D., Paulsson, M., Rosa-Pimentel, E., Sommarin, Y., Wendel, M., Oldberg, Å., and Heinegard, D. (1992). Cartilage matrix proteins: An acidic oligomeric protein (COMP) detected only in cartilage. J. Biol. Chem. 267, 6132-6136. Citations: >330
Aeschlimann, D., and Paulsson, M. (1991). Cross-linking of laminin-nidogen complexes by tissue transglutaminase: A novel mechanism for basement membrane stabilization. J. Biol. Chem. 266, 15308-15317. Citations: >150
Critical Analysis of Research Field
Hadjivassiliou, M, Sanders, D.S., Grünewald, R.A., Woodroofe, N. Boscolo, S., and Aeschlimann, D (2010). Gluten sensitivity: from gut to brain. Lancet Neurol. 9, 318-330. Citations: >120
Aeschlimann, D., and Thomazy, V. (2000). Protein crosslinking in assembly and remodelling of extracellular matrices: The role of transglutaminases. Connect. Tissue Res. 41, 1-27. Citations: >220
Aeschlimann, D., and Paulsson, M. (1994). Transglutaminases: Protein cross-linking enzymes in tissues and body fluids. Thromb. Haemostasis 71, 402-415. Citations: >430
Research Degree Students
Helen Thomas (2000-04, PhD awarded 2004) 'Characterisation of a novel transglutaminase, TGase 6, and determination of its expression pattern' (prize for best short presentation at 7th International Conference on Transglutaminases and Protein Crosslinking Reactions, Ferrara, Italy, 2002)
Kate Silverthorne (2000-04, PhD awarded 2004) 'Development of 'smart' biomaterials for tissue repair' (prize for best presentation at Smith & Nephew research day, York, 2002)
Sally Rosser Davies (2001-05, PhD awarded 2005) 'Novel transglutaminases: a potential route to healthy skin'
Lorna Fiedler (2003-07, PhD awarded 2007) 'The role of decorin in control of endothelial cell behaviour' (prize for best presentation at the Cardiff Institute for Tissue Engineering and Repair (CITER) meeting 2004; prize for best poster at CITER meeting 2005; prize for short presentation at the British Matrix Biology Society meeting, Manchester, 2005; poster prize at the British Matrix Biology Society meeting, Newcastle, 2006)
Anna Koutoulaki (2004-08, PhD awarded 2008) 'Regulation of interleukin-18 signalling in dendritic cells' (poster prize at Cardiff University postgraduate day 2005; Unilever poster prize at BSODR meeting, Durham, 2007)
Jessica Edwards (2005-08 & 2009-10, PhD awarded 2010) 'Role of transglutaminases in signalling that regulates epithelial responses in wound healing'
Anja Bloom (2008-12, PhD awarded 2012) 'CD59a - a novel role in bone' (prize for presentation at Cardiff University postgraduate day 2011)
Magdalena Adamczyk (2009-13, PhD awarded 2013) 'Biomarkers for arthritis: Regulation of transglutaminase activity by non-conventional export' (2nd prize for poster at BSODR meeting, Bath, 2013; Prize for best presentation 5th UK Purine Club Symposium, Cambridge, 2013; awarded Arthritis Research UK Foundation fellowship, 2014-17)
Lea Bauer (2010-14, PhD awarded 2014) 'Characterisation of G protein-coupled receptor 56-signalling and its potential role in tunour progression'
Andreas Heil (2011-2015, PhD awarded 2015) 'Development of a novel 3D human cartilage model system to investigate changes associated with osteoarthritis' (Unilever poster prize at BSODR meeting Bath, 2013; posterprize at Cardiff University postgraduate day 2013)
Ana Mafalda Jegundo dos Reis (2012-) 'The role of transglutaminase 6 in gluten-related disorders'
Rhiannon Griffths (2013-) 'Novel biomarkers for arthritis'
Shannon Tuberville (2015-) 'Unravelling the mechanism by which mutations in transglutaminase 6 cause ataxia'
Dermot Kavanagh (MScD 2005 with distinction) 'An investigation of familial non-syndromic molar oligodontia'
Arash Naseri (MScD 2007 with distinction) 'Towards an understanding of non-syndromic oligodontia'
Nasreen A. Yaqoob (MscD 2010 with distinction) 'Abnormalities in teeth and tooth supporting structures in mice deficient for different matrix proteins'
Selected Conference Presentations
'Osteoarthritis biomarker discovery using a 3D human articular cartilage model' Dewitt, S., Heil, A., Waddington R., Archer, C., and Aeschlimann, D. British Society for Oral and Dental Research Meeting, Cardiff, UK, 2015
'Unconventional protein secretion in innate immunity: The role of P2X7R in transglutaminase 2 export and activation' Griffiths, R., Adamczyk, R., Jones, A., and Aeschlimann, D. British Society for Oral and Dental Research Meeting, Cardiff, UK, 2015
'Transglutaminases: Enzyme externalization and extracellular functions' Aeschlimann, D. American Society for Matrix Biology Meeting, Cleveland, OH, USA, 2014
'Signalling regulating active TG2 release from cells' Adamczyk, M., Dewitt, S., Knäuper, V., and Aeschlimann D. Gordon Research Conference on Transglutaminases in Human Disease Processes, Lucca, Italy, 2014
'Mesenchymal TG2 activates epithelial ADAM17: mechanistic link to G-protein coupled receptor signaling' Bauer, L., Edwards, J., Heil, A., Dewitt, S., Biebermann, H., Knäuper, V., and Aeschlimann, D. Gordon Research Conference on Transglutaminases in Human Disease Processes, Lucca, Italy, 2014
'Signalling regulating extracellular transglutaminase levels' Adamczyk, M., Dewitt, S., Knäuper, V., and Aeschlimann D. Annual Meeting of Molecular Biology Society of Japan, Kobe, Japan, 2013
'Neurological dysfunction in patients with newly diagnosed Coeliac disease: A large prospective study' Hadjivassiliou, M., Hoggard, N., Aeschlimann, P., Sanders, D.S., Curry, S., and Aeschlimann, D. International Coeliac Disease Symposium, Chicago, IL, 2013
'A novel 3D in vitro model of human articular cartilage' Heil, A., Blain, E., Waddington, R., Archer, C., and Aeschlimann, D. British Society for Oral and Dental Research Meeting, Bath, UK, 2013
'TGM6 mutations affect protein structure and activity' Adamczyk, M., Heil, A., Weber, J., Hils, M., Beck, K., and Aeschlimann, D. Gordon Research Conference on Transglutaminases in Human Disease Processes, Davidson, NC, USA 2012