Amyloidosis is a disorder of protein metabolism in which normally soluble proteins are deposited as insoluble fibrils. These amyloid fibrils disrupt the structure and function of affected tissues and lead to serious disease. Systemic amyloidosis is usually fatal and is the cause of about one per thousand deaths in developed countries. Several more common important diseases, including Alzheimer's disease and type II diabetes, are associated with localized amyloid deposition. As yet, there are no specific treatments for any kind of amyloidosis, although a variety of promising pharmacological strategies are under development. AA amyloidosis is the second most common type of systemic amyloidosis in man, occurring in up to 5% of patients with chronic inflammatory diseases. Inflammation dramatically increases production of serum amyloid A protein (SAA) by the liver. When SAA concentrations remain elevated for prolonged periods SAA can be converted into AA amyloid deposits, resulting in systemic AA amyloidosis. By far the most widely used animal model of amyloidosis is murine AA amyloidosis, which very closely resembles human systemic AA amyloidosis. It is an invaluable model for the study of the pathogenesis of amyloidosis and for the evaluation of the new treatments, several of which are currently in development. There is no suitable in vitro model for such testing. In the existing murine model, developed 60 years ago, SAA overproduction is induced by creating persistent inflammation. This requires daily subcutaneous injections of an inflammatory stimulant for up to several weeks, and more rapid induction of amyloid requires more aggressive agents. We propose here to develop, using transgenic techniques, a greatly refined model of AA amyloidosis in which overexpression of an SAA-encoding transgene will be regulated by dietary manipulation (administration or withdrawal of the antibiotic doxycycline). We already have preliminary results suggesting that an appropriate degree of overexpression is feasible. The objectives of the project are first, to optimise the transgenic overexpression of SAA, second, to validate tet-regulatable SAA transgenic mice as a model of amyloidosis, and third, to prepare the model for dissemination. We anticipate that in addition to the welfare benefits, this model will be more consistent and less labour-intensive, advantages that will substantially advance development of new therapies and that it will largely replace existing less satisfactory methods.
- Research Review 2011: A refined mouse model to study systemic amyloidosis
Mazza G, Simons JP, Al-Shawi R, Ellmerich S, Urbani L, Giorgetti S, Taylor GW, Gilbertson JA, Hall AR, Al-Akkad W, Dhar D, Hawkins PN, De Coppi P, Pinzani M, Bellotti V, Mangione PP (2015) Amyloid persistence in decellularized liver: biochemical and histopathological characterization. Amyloid 23(1):1-7 doi:10.3109/13506129.2015.1110518
Campbell-Washburn A.E. et al (2013) Monitoring systemic amyloidosis using MRI measurements of the extracellular volume fraction. Amyloid 20 (2): 93–98. doi:10.3109/13506129.2013.787984
Simons J.P. et al. (2013) Pathogenetic mechanisms of amyloid A amyloidosis. Proc. Nat.l Acad. Sci. 110(40):16115-20. doi: 10.1073/pnas.1306621110.
Campbell A.E. et al (2011) Equilibrium contrast CMR for the detection of amyloidosis in mice. J Cardio Mag Res 13 (Suppl 1): O60. doi:10.1186/1532-429X-13-S1-O60
Simons J.P. et al. (2010) Controllable expression of SAA in transgenic mice: a refined model of systemic amyloidosis. Amyloid 17 (S1): 45–46.
Principal investigatorDr Paul Simons
InstitutionUniversity College London
Co-InvestigatorProfessor Philip Nigel Hawkins
Professor Mark Brian Pepys