Transglutaminases: role in pathogenesis, diagnosis and therapy
The involvement of TGases in neurodegenerative diseases such as Alzheimer's disease, Huntington's disease and Parkinson disease and in tissue fibrosis and scarring like in diabetic nephropathy, is thought to result from a deregulation of enzyme activity leading to loss of tissue homeostasis and the cross-linking and post translational modification of a number of different proteins. Since TGases are thought to be at the centre of the pathogenesis of these different diseases they are considered an important target both for the development of new diagnostics and the development of new therapeutic agents.
The aim of this network is to bring together key groups in Europe both in academic and industry who are actively working in the field of TGase and associated pathologies. By exchange of ideas, trainees, researchers, materials and the organisation of regular meetings, their objective is to gain a deeper understanding of TGases in these different diseases and in so doing develop new diagnostics and therapeutic approaches for their rapid detection and treatment thus providing a European Research Area in the TGases field with collective benefit and competitive advantage.
UNIVERSITA DEGLI STUDI DI ROMA TOR VERGATA
UNIVERSITA DEGLI STUDI DI TRIESTE.
UNIVERSITETET I OSLO
Final Activity Report Summary - TRACKS (Transglutaminases: role in pathogenesis, diagnosis and therapy)
The project has been involved in the comprehensive training of 7 ER's and 7 ESR's and the 7 ESRs are presently in the process of completing their training for the award of a research doctorate The training has involved structured training courses in research skills and techniques, generic and transferable skills. These include entrepreneurship, bioethics, business acumen and courses in the Bench to Market processes. The project has piloted an early point of care test for celiac sufferers and provided new diagnostics for TGases detection. Anibiotech (an associated company) has now developed the Biocard Celiac test for commercial sale. A further prototype kit has also been developed by Partner Covalab for measuring human IgA anti TG2 in Celiac disease which is now commercially available. The major celiac epitope of TG2 has been characterised and patented which will result in a more reliable diagnostic for the testing of celiac suffers eventually avoiding invasive surgery.
The project has provided cloned human antibodies against TG2 via the construction of phage display antibody libraries from lymphocytes and via this novel technique has established a new method for identifying TG2 binding partners. A number of new molecules have been synthesised and tested that are able to block the activity of different TGases. These have been shown to be effective in pre -clinical studies of kidney scarring, diabetic nephropathy and Huntingtons disease and have the potential to be used as future drugs to treat these TGase related diseases. Importantly, these compounds appear to be more active and specific than those produced in earlier research and appear nontoxic and easy to use in experiments. The inhibitors have also established proof of concept of TGase 2 involvement in fibrosis and scarring and other TGase 2 related pathologies. New cell culture models for the study of intraneuronal inclusion formation that occur in neurodegenerative diseases have been developed and tested with a view to the rapid screening of these new TGase inhibitors thus minimising the need for animal testing.
Partners involved: Aston University, Birmingham England (Coordinator); University of Tor Vergata, Rome, University of Trieste, Italy; University of Tampere, Finland; Covalab (SME) Lyon, France; University of Debrecen, Hungary; University of Oslo, Norway; X-Link (SME), Nottingham, England.
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