The systemic amyloidoses is a heterogeneous group of diseases, all characterized by deposition in many tissues and organs of a principally extracellular, pathological substance, called amyloid. The amyloid is an insoluble, fibrillar form of one of more than 25 normally soluble proteins. The fibril protein in the amyloid is more or less misfolded and contains an unusually high degree of beta-sheet, allowing molecules to assemble into long, rigid and resistant fibrils. The pathogenesis is still unclear but overproduction of the amyloidogenic protein and destabilization of the tertiary structure by mutations is often involved. The general aim of this proposal is to use recently obtained knowledge of the human genome and its products to understand the nature of systemic amyloidoses. The aim is also to translate this basic knowledge on proteins, protein folding and protein interaction into the clinical situation in order to develop safe diagnostic methods and new treatments for this group of usually deadly diseases. This will be done by a collective effort of a group of European scientists, covering the whole field from molecular mechanisms to clinicians devoted to treatment of patients with systemic amyloidosis. Basic studies will performed with advanced biochemical and biophysical methods including e.g. plasmon-resonance-based techniques and nuclear magnetic resonance (NMR) spectroscopy. Knowledge from basic studies will be translated into biological systems in order to elucidate mechanisms by which aggregated proteins are deleterious to cells and for these studies, cell cultures and transgenic organisms (mice, Drosophila) will be used. These systems will also be used for development of evaluation of methods to interfere with development of amyloid. The mutual effort also aims to increase the general awareness of the systemic amyloidoses, today often diagnosed late in disease, and to further develop simple and safe diagnostic methods.
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