Prof Daniel Aeschlimann
Telephone:+44 (0)2920 74 4240
Fax:+44(0)2920 74 4509
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 “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”:
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.