Objetivo
Understanding molecular basis of alcohol addiction still remains a great challenge for science and at the same time the only chance for designing successful molecular therapy. Calcium and calmoduline-dependent kinase II alpha (alpha CaMKII) is a major protein of forebrain glutamatergic neurons with well established function in various aspects of cell physiology, e.g. actin remodelling. Alcohol-induced actin remodelling has been recently implicated in control of alcohol resistance and consumption in mice. Interestingly, we have found that mice with mutated autophosphorylation domain (T286A) of alpha CaMKII (Giese et al., 1998) have decreased basal level of polymerized actin as well as alcohol consumption and preference (Radwanska, unpublished observations). Thus we would like to hypothesis that alpha CaMKII autophosphorylation is a key modulator of alcohol-induced actin-remodelling and thus alcohol consumption and preference. To verify our hypothesis we shell accomplish the following objectives: - to test whether autophosphorylation of alphaCaMKII regulates acute behavioural response to alcohol as well as to long-term alcohol drinking; - to identify brain regions in which autophosphorylation of alphaCaMKII contributes to actin remodelling; - to investigate which signalling pathways connect CaMKII autophosphorylation in mutant mice with actin remodelling; - to test whether autophosphorylation of alphaCaMKII regulates actin remodelling induced by alcohol; Here we will establish the role of CaMKII autophosphorylation in actin remodelling and alcohol preference. Toward this end, integrative approach will be used: behavioural studies with mutant mice (CaMKIIT286A) will be combined with various molecular and biochemical analyses of protein expression and phosphorylation. This research will advance our understanding of molecular basis of alcohol preference and alcohol consumption, which are the critical prerequisites for alcohol addiction.
Ámbito científico
Convocatoria de propuestas
FP7-PEOPLE-2009-RG
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Régimen de financiación
MC-ERG - European Re-integration Grants (ERG)Coordinador
02 093 Warszawa
Polonia