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.
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
- natural sciences biological sciences neurobiology
- natural sciences biological sciences zoology mammalogy
- medical and health sciences basic medicine physiology homeostasis
- natural sciences biological sciences biochemistry biomolecules proteins enzymes
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Programme(s)
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
Topic(s)
Calls for proposals are divided into topics. A topic defines a specific subject or area for which applicants can submit proposals. The description of a topic comprises its specific scope and the expected impact of the funded project.
Calls for proposals are divided into topics. A topic defines a specific subject or area for which applicants can submit proposals. The description of a topic comprises its specific scope and the expected impact of the funded project.
Call for proposal
Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.
Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.
FP7-PEOPLE-2013-CIG
See other projects for this call
Funding Scheme
Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
MC-CIG - Support for training and career development of researcher (CIG)
Coordinator
7610001 Rehovot
Israel
The total costs incurred by this organisation to participate in the project, including direct and indirect costs. This amount is a subset of the overall project budget.