FP6 priority

1.1.1   Genomics and Biotechnology for Health

Title of the proposal

Role of postischemic disturbances in protein synthesis on the metabolic and functional recovery of CNS. Mechanisms of protein synthesis inhibition in the selectively vulnerable brain regions

Institute

Slovak Academy of Sciences, Institute of Neurobiology
Soltesovej 4, 040 01 Kosice, Slovak Republic

Contact

Research subject for a potential FP6 project

The project is aimed to advance in the knowledge of the possible mechanisms implicated in the inhibition of translation occuring during the reperfusion phase. A model of transient forebrain ischemia (Pulsinelli’s four vessel occlusion), 30 min of ischemia followed by reperfusion times of 15 and 30 min and 2, 4 and 6 hours, as well as a sublethal 4-5 minutes ischemic preconditioning will be used. The study will be performed in different extracts prepared from cortex (resistant regions) and hippocampus (vulnerable regions). The neuroprotective effect of growth factors and proteases inhibitors on protein synthesis will be determined. The following parameters will be determined in different crude preparations: “in vitro” protein synthesis rate, levels and phosphorylation status of initiation factors eIF-2, eIF-2B, eIF4E, 4E-BP1, eIF-4G. In addition, we will try to identify the kinase and phosphatase activities responsible for the phosphorylation of the factors. The activity of factors such as eIF4E and eIF4G is also regulated by proteolitic degradation and we will studied the possible proteases implicated calpain or caspases. Furthemore we will achive the role of factors eIF2 and eIF4E/4G in the selective translation of mesengers during translational repression which could be related with survival and neuronal death.

Recent international cooperation of the research team

Dr. M. Salinas, Hospital Ramon y Cajal, Department of Biochemistry, Madrid, Spain
Prof. J. L. Fando, University Alcala, Department of Biochemistry and Molecular Biology, Alcala de Henares, Spain

Proposer´s relevant publications related to the research subject

BURDA J., MARTIN M.E., GARCIA A., ALCAZAR A., LFANDO J. and SALINAS M.: Phosphorylation of the alpha subunit of initiation factor 2 correlates with the inhibition of translation following transient cerebral ischaemia in the rat. Biochem J., 302,1994,335-338

BURDA J., MARTIN M.E., GOTTLIEB M., CHAVKO M., MARSALA J., ALCAZAR A., PAVON M., FANDO J.L. and SALINAS M.: The intraischemic and early reperfusion changes of protein synthesis in the rat brain. eIF-2 alpha kinase activity and role of initiation factors eIF-2 alpha and eIF-4E. J Cereb Blood Flow Metab., 18,1998,59-66

MARTIN DE LA VEGA C., BURDA J. and SALINAS M.: Ischemia-induced inhibition of the initiation factor 2a phosphatase activity in the rat brain. NeuroReport., 12,2001,1021-1025

MARTIN DE LA VEGA C., BURDA J., NEMETHOVA M., QUEVEDO C., ALCAZAR A., MARTIN M.E., DANIELISOVA V., FANDO J.L. and SALINAS M.: Possible mechanisms involved in the down-regulation of translation during transient global ischaemia in the rat brain. Biochem J., 357,2001,819-826