Reversal of aberrant neurogenesis by glucocorticoids and microRNAs: relevance for the treatment of epilepsy
11 / 2009 - unknown
Based on recent reports demonstrating that alteration in neurogenesis may be treatable using genetic manipulations, I propose aberrant neurogenesis as an attainable and innovative drug target for treating epilepsy. I will use RNA-interference in combination with lentiviral vectors to modulate miRNA expression in individual newborn neurons in vivo. I will apply this to experimental models of epilepsy where aberrant neurogenesis is induced, in an integrative genomic, microRNA and proteomic approach to understand the roles of glucocorticoid receptors and microRNAs in neurogenesis. The importance of RNA interference and microRNAs has been shown only in the last decade, demonstrating the novelty of this whole field. Already I demonstrated that hippocampal neurogenic cells express specific mechanisms to control glucocorticoid signal, that brain-specific microRNAs control the expression of glucocorticoid receptor and that adequate glucocorticoid receptor levels are crucial to prevent aberrant neurogenesis. Neurogenesis, the generation of neurons, is a delicately controlled process. In the adult hippocampus, a complex balance of factors keeps it within physiological range. In pathological situations, neurogenesis is aberrantly induced. This is well proven in animal models of epilepsy. This aberrant neurogenesis correlates with hallmarks of epilepsy in human brain. Alterations in neurogenesis are not unique to the epileptic brain. Alterations have been linked to other neurologic disorders such as addiction, stress and depression, stroke, schizophrenia and others. The study of the interplay between glucocorticoid receptors and brain-specific microRNAs in the regulation of neurogenesis will give insight into the role of neurogenesis in neuropathology and may provide new, more specific and selective therapeutic intervention points for associated diseases. I will develop my results into innovative drug targets for anti-epileptic therapies. My ideas count with support from The Epilepsy Institutes of the Netherlands Foundation, UCB Pharma B.V and financial match of the hosting institution, Leiden Amsterdam for Drug Research (LACDR), Leiden University.