ENDOGENOUS AED

Supply-rate depression as endogenous anti-epileptic mechanism

Coordinatore	FYZIOLOGICKY USTAV AKADEMIE VED CESKE REPUBLIKY VEREJNA VYZKUMNA INSTITUCE (VVI)    more  Organization address address: VIDENSKA 1083 city: PRAHA 4 postcode: 142 20 contact info Titolo: Ms. Nome: Lucie Cognome: ?iperová Email: send email Telefono: +420 241 062 817
Nazionalità Coordinatore	Czech Republic [CZ]
Totale costo	100˙000 €
EC contributo	100˙000 €
Programma	FP7-PEOPLE Specific programme "People" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013)
Code Call	FP7-PEOPLE-2012-CIG
Funding Scheme	MC-CIG
Anno di inizio	2012
Periodo (anno-mese-giorno)	2012-09-01   -   2017-08-24

 Partecipanti

#	participant	country	role	EC contrib. [€]
1	FYZIOLOGICKY USTAV AKADEMIE VED CESKE REPUBLIKY VEREJNA VYZKUMNA INSTITUCE (VVI)  Organization address address: VIDENSKA 1083 city: PRAHA 4 postcode: 142 20 contact info Titolo: Ms. Nome: Lucie Cognome: ?iperová Email: send email Telefono: +420 241 062 817	CZ (PRAHA 4)	coordinator	0.00
2	FUNDACION PARA LA INVESTIGACION MEDICA APLICADA FIMA  Organization address address: AVENIDA DE PIO XII 55 city: PAMPLONA postcode: 31008 contact info Titolo: Ms. Nome: Ana Cognome: Iglesias Email: send email Telefono: +34 948 194700	ES (PAMPLONA)	participant	100˙000.00

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 Obiettivo del progetto (Objective)

'Epilepsy is a prevalent neurological disorder affecting more than 1 % of all people, with the estimated number of 900,000 children and adolescents suffering from active epilepsy in Europe. Most current drugs targeting this disease have important adverse side-effects. An ideal drug would, however, potentiate the endogenous anti-seizure mechanisms that keep most humans epilepsy-free.

To date, these native “anti-seizure mechanisms” have not been identified. Recently, a novel candidate mechanism termed “supply-rate depression” was functionally characterized. It is only induced by excessive synaptic use, after which it dampens all pre-synaptic function for several minutes.

This proposal would test whether lowering the threshold for inducing supply-rate depression is protective against epilepsy using genetically engineered mice, and will additionally test a structure/function hypothesis related to the assembly of the vesicles in presynaptic terminal that could lead to a high-throughput drug screen.

These goals will be accomplished via the following Specific Aims: 1. To generate a synapsin 2 conditional knockout mouse line where synapsin 2 is deleted exclusively at excitatory synapses and thereby speed the onset of the protective mechanism at excitatory synapses. 2. To evaluate the susceptibility to seizures of the synapsin 2 conditional knockout mice using chemically induced models of epilepsy. 3. To apply state-of-the-art electron microscopy tomography techniques to test the structure/function hypothesis that the lengths of presynaptic vesicle tethering units are ~ 40% shorter in presynaptic terminals of synapsin 2 knockout synapses.

Results of this project may justify a large-scale industrial effort for developing a new generation of anti-epileptic drugs that target supply-rate depression. Thus, these new substances should have reduced occurrence and magnitude of unwanted side effects and would immensely improve the well-being of affected people.'