IBMC, Portugal
Maria Joao Saraiva
E-mail: mjsaraiv@ubmc.up.pt
Phone: + 351 22 6074900
Overall research program
Dr. Saraiva will participate with unique mouse models for TTR related amyloidosis testing pathogenic aspects of this group of diseases, such as the role of fragmentation in amyloidogenesis, and efficiency of therapeutics, testing the effect in amyloidogenesis and tissue toxicity of different drugs provided by the other participants. Her lab skills are described in publications and include genetic epidemiology, structure and function of TTR, development of effective therapies for FAP, study of TTR amyloidogenesis, pathophysiological consequences of amyloid deposition and modulator factors of phenotypic expression.
Five key publications
1. Sousa MM, Barbas do Amaral J, Guimarães A, Saraiva MJ. Upregulation of the
extracellular matrix remodelling genes, biglycan, neutrophil gelatinase-associated
lipocalin and matrix metalloproteinase-9 in familial amyloid polyneuropathy. FASEB
J. 19: 124-126, 2005
2. Almeida MR, Macedo B, Cardoso I, Alves I, Valencia G, Arsequell G, Planas A,
Saraiva MJ. Effective and selective action of a iodinated diflunisal derivative in
transthyretin binding and tetramer stabilization in serum from familial amyloidotic
polyneuropathy patients. Biochem J 381: 351-356, 2004.
3. Cardoso I, Merlini G, Saraiva MJ. 4’-iodo-4’-Deoxydoxorubicin and tetracyclines
disrupt transthyretin amyloid fibrils in vitro producing non- cytotoxic species.
Screening for TTR fibril disrupters. FASEB J 17: 803-809, 2003
4. Sousa MM, Fernandes, R, Palha JA, Taboada A, Vieira P, Saraiva MJ Evidence for
early cytotoxic aggregates in transgenic mice for human transthyretin Leu55Pro.
Am J Pathol 161:1935-48, 2002.
5. Sousa MM, Cardoso I, Fernandes R, Guimarães A, Saraiva MJ. Deposition of
transthyretin in early stages of familial amyloidotic polyneuropathy: evidence for
toxicity of non-fibrillar aggregates. Am J Pathol 159:1993-2000, 2001.
Ana Damas
IBMC, Portugal
E-mail: amdamas@ibmc.up.pt
Phone: + 351 226 074900
Overall research program
Using X-ray crystallography, fibre diffraction, XANES, FTIR and microscopy, we plan to get better insight into the molecular mechanisms leading to protein aggregation in transthyretin (TTR) amyloidosis. Better insight on new diagnosis and therapeutical strategies will be achieved.
Therefore, the following tasks will be carried out: i) TTR variants with different propensity for amyloid formation will be designed, produced and studied by X-ray crystallography, in order to clarify the structural alterations that are important in the amyloidogenic pathway;
ii) Analysis of TTR amyloid fibres, produced “in vitro” and in different ways;
iii) The three-dimensional structure of TTR complexed with different aggregation inhibitors and fibre disrupters;
iv) Molecular modeling of new tools for diagnosis and therapy.
Five key publications
1. Sebastião MP, Saraiva MJ, Damas AM. The crystal structure of amyloidogenic
Leu55Pro transthyretin variant reveals a possible pathway for TTR polymerisation
into amyloid fibrils. J Biol Chem 273:24715-24722, 1998
2. Gales L, Cardoso I, Fayard B, Quintanilha A, Saraiva MJ, Damas AM. X-ray
absorption spectroscopy reveals a substantial increase of sulfur oxidation in TTR
upon fibrillization. J Biol Chem 278:11654-11660, 2003
3. Morais-de-Sa E, Pereira PJB, Saraiva MJ, Damas AM. The crystal structure of
transthyretin in complex with diethylstilbestrol: a promising template for
the design of amyloid inhibitors. J Biol Chem 279:53483-53490, 2004
4. Gales L, Macedo-Ribeiro S, Arsequell G, Valencia G, Saraiva MJ, Damas AM. Human
transthyretin in complex with iododiflunisal – structural features associated
with a potent amyloid inhibitor. Biochem J 388, 615-621, 2005
5. Maia F, Almeida MR, Gales L, Kijjoa A, Pinto MMM, Saraiva MJ, Damas AM. The
binding of xanthone derivatives to transthyretin. Biochem Pharmacol 70:1861-
1869, 2005