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An  exciting point  is how cells can detect and sense stress in order to trigger a proportional response, in terms of intensity and duration. So, although stress response is in principle pro-survival, overexposure to intense stress can lead to cell death.  Moreover, mild episodes of stress accumulated during the lifetime may preconditioning cells and tissues to better response against future acute stress (the hormesis concept). This opens the possibility to intervene the ageing process or extend the lifespan through the  modulation of the stress response.

 

 

About stress.....

 

To survive, all living organisms must respond appropriately to environmental and endogenous stress that can potentially damage proteins, genomes or cell membranes. Radiation, starvation, chemicals, but also free radicals generated by catabolic processes can  trigger adaptive responses in gene expression to provide cells with a toolkit for molecular repair, that include chaperones, antioxidant proteins, enzymes involved in DNA repair, in amino acid metabolism and in protein synthesis. In the short term, stress response is devoted to organism survival, but in the long term cumulative responses to stress during the lifetime can exert a profound effect on ageing rates and lifespan. So much so that stress response likely have been shaping the evolution of living organisms on earth.  

 

About translation.....

 

Far from being an automatic process, protein synthesis is strictly controled at both global and message-specific manner. The abundance and activity of ribosomes and associated initiation factors (eIFs) depend on the metabolic state of the cell, the availability of nutrients and mitogens, and even on the cell type. Translation rates of a given mRNA can be under the control of sequence and secondary RNA structure motifs that regulate the recruitment of mRNA to ribosomes. Translation is intimately connected to other postranscriptional processes such as protein folding and secretion, mRNA surveillance, mRNA stability and storage. Translation rates are rapidly adjusted to environmental changes and stress cues, mainly by regulating the activity of initiation factor 2 (eIF2) through phosphorylation. The activity of eIF2 can regulate translation in both global and mRNA-specific manner.

 

 

Our scientific objectives.....

 

  • Understanding how cells can detect and sense UV radiation, nutritional starvation and other stress by activating eIF2 kinases

  • A comprehensive description of translation reprogramming during stress response in mouse and fission yeast

  • Identification of cis-acting elements (sequences and structures) in mRNAs, and the trans-acting factors (alternative eIFs) involved in stress-specific translation

  • Probing global mRNA structure (structurome) by means of high throughput techniques

  • Defining the relationships between translation, stress response and ageing by means of genetic models in mice and fission yeast

  • Exploring the connections of eIF2alpha kinases with other pathways that also sense stress such as mTOR and MAPKs

  • Alleviating age-related pathologies by modulating stress response and translation in mice

 

 

Our models and approaches....

 

  • Mammalian cell cultures, mice and fission yeast

  • Ribosome profiling 

  • SILAC and other proteomic techniques

  • Gene targeting and interference by lentiviral transduction

  • Bioinformatic tools and Systems Biology

  • Structural analysis of mRNA and ribosomes

 

 

 

 

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