instituto de biologia molecular e celular | institute for molecular and cell biology
Previous research results:
Studies transthyretin (TTR)-related degenerative diseases and the role of amyloidogenesis inhibitory and enhancing factors in disease development. In particular, we focus on familial amyloidotic polyneuropathy (FAP) an autosomal dominant disease related to TTR mutations, prevalent in Portugal. Other lines of research devote to signalling pathways involved in brain injury, particularly those related to Alzheimer disease, brain ischemia, and oxidative conditions using unique animal models and seek neuroprotective strategies to rescue phenotypes related to these conditions. Specific objectives:
- To identify unknown ligands of TTR important in the biology of the protein in health and disease by determination of TTR- protein ligand interactions both “in vitro” and “in vivo” using a TTR-KO mouse model.
- To understand why TTR has propensity to aggregate as amyloid fibrils through studies of intermediate forms in TTR amyloidogenesis and effect of inhibitory and enhancing factors.
- To generate newer improved models for FAP for investigation on signalling cascades triggered by TTR aggregates, for biochemical markers of the disease, for elucidation of neurodegeneration, and to test newer drugs/protocols to inhibit cytotoxicity in tissues related to amyloid deposition.
- To understand neuroprotection of TTR in Alzheimer disease and in ischemia; to understand neuroprotection in models of oxidative stress.
IMAGE: TTR amyloid plaque in the nerve of a FAP patient (green) and up-reagulation of head shock protein HSP 27 (red)
Future research goals:
We will foccus on Neurodegeneration and Neuroprotection: We will dissect molecular pathways triggered by TTR aggregates and forms to ameliorate cell death; these studies encompass indepth knowledge of unknown functions of TTR in the nervous system; will seek for the molecular basis of neuroprotective properties of TTR in the nervous system; we will follow on with the characterization of acyl-L-carnitine neuroprotective properties.
A large effort of the Group is on translational medicine on unique pre-clinical models for FAP, and participation on clinical trials on FAP patients. For that purpose we collaborate with international up-front companies in the development of new therapeutic and prophylatic drugs in the treatment of protein misfolding disorders.
Gonçalves N, Teixeira-Coelho M, Saraiva MJ. The inflammatory response to sciatic nerve injury in a Familial Amyloidotic Polyneuropathy mouse model. Exp Neurol. 257: 76-87, 2014
Saraiva MJ, Magalhães J, Ferreira N, Almeida MR. Transthyretin deposition in familial amyloidotic polyneuropathy. Current Medicinal Chemistry. 19: 2304-2311, 2012.
Ferreira N, Saraiva MJ, Almeida MR. Epigallocatechin-3-gallate as a potential therapeutic drug for TTR-related amyloidosis: “in vivo” evidence from FAP mice models. Plos One 7(1): e29933. 2012
Cardoso I, Martins D, Ribeiro T, Merlini G, Saraiva MJ. Synergy of combined Doxycycline/TUDCA treatment in lowering Transthyretin deposition and associated biomarkers: studies in FAP mouse models. J Translational Medicine. 8: 74-78, 2010
Santos SD, Lambertsen KL, Clausen BH, Akinc A, Alvarez R, Finsen B, Saraiva MJ. Cerebrospinal fluid transthyretin neuroprotection in a mouse model of brain ischemia. J Neurochem 115: 1434 – 1444, 2010.
Santos SD, Fernandes R, Saraiva MJ. The heat shock response modulates transthyretin deposition in the peripheral and autonomic nervous systems. Neurobiology of Aging. 31(2):280-289, 2010.
Almeida, M. Rosário
Gomes, João Carlos
Alexandra Pereira Teixeira, Cristina
Peixoto Gomes, Joana
Filipa Pereira Bezerra, Carla
Meira Gonçalves, Paula
Pedro da Silva Moreira, João
Sofia Martins, Helena