The purpose of this proposal is to create an animal model in mice for TTR-associated amyloidosis leading to FAP with the long-term goal to generalise the model for other amyloid disease.
Amyloidoses are diseases of protein conformation. 16 amyloidogenic proteins are known of which the a-amyloid precursor peptide in Alzheimer's disease and the plasma protein transthyretin (TTR) in different forms of familial amyloidosis are best known. Both are associated with neurodegenerative lesions for which there is no cure. They both affect quality of life of individuals and causes large costs for the health care system.
TTR is associated with two types of amyloidosis occurring in different time periods of life. The senile form (Senile systemic amyloidosis, SSA) affects 25% of all individuals over the age of 80 years and has mainly manifestations in the heart. It is not a genetic disease, and it is thought that amyloid results from an inherent propensity of TTR to form amyloid with time. The genetic form is dominant autosomal and occurs earlier in life. More that 50 mutations of TTR are known and are associated with familial amyloidosis either with polyneuropathy (FAP) or cardiomyopathy (FZC), diseases with extracellular amyloid fibrils composed of TTR. The most frequent mutation is an exchange of valine for methionine in amino acid position 30 (TTR Met30). The specific objectives are:
1. study mechanisms for amyloid formation as result of point mutations of the TTR gene;
2. to study mechanisms for amyloid formation well as its consequences by developing a transgenic mouse model with overexpressed and mutated TTR genes and by studies of effects on cultured cells;
3. to develop diagnostic and therapeutical reagents.
The project involves creation of highly amyloidogenics mutants of TTR, studies of their structure, use of transgenic mice with amyloidogenic mutations, studies of pathophysiological consequences of amyloid deposits and the development of new therapeutic strategies based on the anthracycline derivative IDOX.
familial amyloidosis with polyneuropathy; cardiomyopathy; senile systemic amyloidodis; transthyretin; autosomal dominant; in vitro mutagenesis; transgenic mice; 3-dimensional structure; calorimetry; NMR; IDOX; anthreacyclin.