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Developing therapies for Nitric Oxide (NO) related neurodegeneration

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.

Coordinator

WEIZMANN INSTITUTE OF SCIENCE

Address

Herzl Street 234
7610001 Rehovot

Israel

Activity type

Higher or Secondary Education Establishments

EU Contribution

€ 100 000

Administrative Contact

Gabi Bernstein (Ms.)

Project information

Grant agreement ID: 618113

Status

Closed project

  • Start date

    1 October 2013

  • End date

    30 September 2017

Funded under:

FP7-PEOPLE

  • Overall budget:

    € 100 000

  • EU contribution

    € 100 000

Coordinated by:

WEIZMANN INSTITUTE OF SCIENCE

Israel