NO-BRAINER

Developing therapies for Nitric Oxide (NO) related neurodegeneration

Coordinatore	WEIZMANN INSTITUTE OF SCIENCE    more  Organization address address: HERZL STREET 234 city: REHOVOT postcode: 7610001 contact info Titolo: Ms. Nome: Gabi Cognome: Bernstein Email: send email Telefono: +972 8 934 4026 Fax: +972 8 934 4165
Nazionalità Coordinatore	Israel [IL]
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-2013-CIG
Funding Scheme	MC-CIG
Anno di inizio	2013
Periodo (anno-mese-giorno)	2013-10-01   -   2017-09-30

 Partecipanti

#	participant	country	role	EC contrib. [€]
1	WEIZMANN INSTITUTE OF SCIENCE  Organization address address: HERZL STREET 234 city: REHOVOT postcode: 7610001 contact info Titolo: Ms. Nome: Gabi Cognome: Bernstein Email: send email Telefono: +972 8 934 4026 Fax: +972 8 934 4165	IL (REHOVOT)	coordinator	100˙000.00

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 Obiettivo del progetto (Objective)

'Nitric oxide (NO) is an essential signaling molecule for diverse physiological and disease processes. The current paradigm of NO regulation focuses at the level of nitric oxide synthase (NOS). However, the respective unique or combined genetic deficiencies of the NOS isoforms exhibit relatively modest phenotypes in mice. Moreover, approaches targeted at modulating NOS activities have not successfully translated into therapy. All NOSs isoforms use arginine as the sole substrate for NO production and interestingly, only one enzyme in mammals- argininosuccinic acid lyase (ASL) synthesizes endogenous arginine. In humans, ASL deficiency (ASLD) causes argininosuccinic aciduria, the second most common urea cycle disorder. In stark contrast to other urea cycle disorders, patients with ASLD show systemic and chronic features even with good metabolic control. We recently demonstrated a new structural requirement of ASL for maintenance of a NO synthetic complex necessary for generation of NO from both intracellular and extracellular sources of arginine. Thus, in the absence of ASL, there is decreased NO signaling. Importantly, we were able to translate our findings in a clinical therapeutic human context by supplementing an ASA patient with NO donors and improving his cardiovascular and neurocognitive functions. We now hypothesize that regulating ASL would allow us to characterize the cellular and molecular mechanisms underlying the NO flux at normal and pathological conditions, for therapeutic applications. Using a novel conditional knockout model of Asl, we are now uniquely positioned to dissect the cellular contribution of NO metabolism to different disease pathogenesis. As a proof of concept, we will start by dissecting NO metabolism in the central nervous system at homeostasis and in acute and chronic brain injury. Undoubtedly, our results will provide a novel approach for the study of other NO related disorders, with therapeutic application.'