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The ongoing reseach project focuses on the role of neuronal cell adhesion molecules (NCAMs) in normal and dysfunctional brain plasticity with the aim of developing compounds with a beneficial effect on diseases involving neurodegeneration, cognitive and emotional impairment.We propose that the exposure of the developing or adult brain to various traumatic factors induces long-lasting perturbations in the expression of NCAM and its polysialylated form PSA-NCAM and thereby affect proliferation, migration,differentiation and formation of appropriate neuronal networks in the brain. To study this we will use varoius animal models with impaired neuronal plasticity due to early postnatal stress or toxin treatment and investigate causal link between NCAM and PSA NCAM signalling mashinery and neuronal organization in several brain regions (hippocampus, amygdala, cortex) by means of double immunochistochemistry combined with laser confocal microscopy. To establish the mechanisms by which NCAMs signalling system controls neuronal plastity we will use genetic and pharmacological approaches aimed at compensating deficiency in the neuronal plasticity. Using genetic approach we will produce double transgenic mice: NCAM deficient + TRK-B (receptor for brain derived neurotrophic factor) -overexpressing mice via cross-breeding and study whether enhancement in the BDNF signalling will compensate for the impaired brain plasticity in NCAM deficient mice. Using pharmacological approach we will test several molecules (NCAM-mimetics) in in vitro and in vivo models of impaired neuronal plasticity. The perspective compounds will be patented and used as drug prototypes for the correction of cognitive function in various neurodegenerative diseases. |