Apoptosis induïda per ceramida enn cèl·lules del sistema nervios estudi de l'alteració del metabolisme de la fosfatidilcolina com a mecanisme desencadenant i guia per al desenvolupament d'estratègies

  • Picatoste Ramón, Fernando (Principal Investigator)
  • Pardo Pardo, Raúl (Scholar)
  • Claro Izaguirre, Enrique (Investigator)
  • Claudia Altamirano Gómez (Investigator)
  • Sarri Plans, Elisabet (Investigator)

Project Details

Description

This research proposal addresses the role that altered phosphatidylcholine metabolism plays in the mechanisms whereby ceramide triggers apoptosis in nerve cell, with the aim to develop cytoprotective strategies baded on the modulation of the phosphatidylcholine synthesizing pathway. Our own previous observations show that: i) Apoptosis induced by a cell permeable ceramide analog (C2-ceramide) in cerebellar granule neurons takes place with a concomitant inhibition of phosphatidylcholine synthesis. ii) Depletion of extracellular potassium, which induces apoptosis in these same cells, does not affect phosphatidylcholine synthesis. iii) Addition of exogenous phosphatidylcholine prevents fully the loss of cell viability induced by C2-ceramide: in contrast, cells undergoing low potassium-induced apoptosis are not resued by exogenous phosphatidylcholine.iv) Apoptosis induced by raising endogenous ceramide levels after inhibition of ceramidase or by addition of sphingomyelinase can be also reverted with exogenous phosphatidylcholine. Based on these seminal results, and also on data from other research groups indicating that a variety of cytoxic drugs share the property to inhibit phosphatidylcholine metabolism, we propose the following specific goals: 1) to ascertain whether inhibition of phosphatidylcholine synthesis is a primary event in the ceramide-induced apoptotic cascade. 2) to establish a common pattern in the time course of appearance of apoptotic markers as triggered by different drugs which inhibitphosphatidylcholine synthesis -i.e, ceramide, famesolk, hexadecylphosphocholine, ET18 OCH3. 3) To identify the phosphatidylcholine-syynthesizing or degrading reactions affected by ceramide. 4) To explore the mechanisms whereby phosphatidylcholine exerts its cytoprotective action.
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StatusFinished
Effective start/end date28/12/0127/12/04

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