SRF target genes in epilepsy
Start date: Jun 1, 2009,
End date: Nov 29, 2013
The aim of this project is to identify genes regulated by SRF (Serum Response Factor) in the epilepsy. Epilepsy is a chronic neurological disorder, affecting 1-3% of human population with temporal lobe epilepsy (TLE) being the most common type in adults. Unfortunately, current anti-epileptic drugs are ineffective in more than 70% of TLE patients. Therefore, it is very important to understand the molecular mechanism underlying the pathology. Multiple pieces of evidence imply that aberrant synaptic plasticity may underlay epilepsy. Inactivation of SRF was shown to cause deficiency in hippocampal synaptic plasticity and learning. In addition, impaired axonal outgrowth, guidance and synaptic targeting has been reported. SRF was also suggested to be crucially involved in neurological disorders like epilepsy. The proposed project is based on the hypothesis that regulation of gene transcription by SRF, will play a crucial role in the aberrant plasticity observed in epilepsy. To confirm this hypothesis we will (i) identify new target genes regulated by SRF in the animal model of aberrant neuronal plasticity by microarray studies, (ii) confirm results obtained by global gene expression analysis using methods Q-RT-PCR, CHIP assay, in situ hybrydization and immunohistochemistry, (iii) further characterize the function of SRF-dependent effector proteins in synaptic plasticity (dendritic spines formation / neurite outgrowth). Our data will have an impact on the current understanding of the pathogenesis of epilepsy, as well as influence the development of new therapeutic opportunities by selectively targeting aberrant plasticity-related SRF effectors. Moreover, the results obtained by global analysis may become an excellent starting point of many new basic research avenues. We will use a multidisciplinary approach in which inducible gene inactivation methods will be combined with the elements of bioinformatic analysis, molecular biology as well as high resolution imaging.
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