Excitotoxic neuronal cell death
Excitotoxicity contributes significantly to neuronal cell death in a number of neurological conditions including stroke, head trauma, and Huntington's disease. The recent discovery of the proteins that anchor and interact with glutamate receptors opens for a new strategical approach to cytoprotective therapy. The present project aims at exploiting this conceptual advance to provide a platform for cytoprotective therapies that do not interfere unduly with synaptic transmission.
Glutamate receptor interacting proteins ("interactors") serve dual purpose. They determine the level and site of glutamate receptor expression within the cells and connect the receptors to specific intracellular signalling pathways. Both roles are interesting from a therapeutical perspective. Thus, excitotoxicity might be alleviated by modulation of the surface expression of glutamate receptors, as well as by interfering with their downstream signalling.
The first part of the project aims at providing a more complete picture of the functional roles of interactors. It is envisaged that we will be able to identify novel interactors and that we will be in a position to understand, at a molecular level, how the different interactors connect with glutamate receptors and with each other. This part of the project will also elucidate the principles that govern the turnover and surface expression of glutamate receptors and the mechanisms that couple the individual receptors to specific downstream effectors of excitotoxisity.
The second part aims at exploiting the increased insight obtained through the first part of the project to design ways to alleviate excitotoxicity in different model systems. In designing these experiments the complex of glutamate receptor interacting proteins will be viewed as a "nodal point" in orchestrating the surface expression of receptors and in activating appropriate and inappropriate (excitotoxic) signalling pathways.
The present project will be based on a unique combination of methods that draw full advantage of the technological advances made over the last few years.