Project description
Accelerating drug discovery for brain disorders
The chloride importer (Cl) NKCC1 and the Cl exporter KCC2 help regulate neuronal chloride concentration. A defective ratio seems to be behind many neurological diseases, such as several brain disorders. Moreover, NKCC1 inhibition by the FDA-approved diuretic bumetanide rescues many symptoms in animal models. However, this requires chronic treatment, which poses crucial issues for drug compliance, given the diuretic effect of bumetanide caused by the inhibition of the kidney-specific Cl transporter NKCC2. In this context, the EU-funded 3D NKCC1 project will provide insights into the structure-function relationships of NKCC1 in terms of ion transportation. The results will critically accelerate the discovery of new and urgently needed drugs for brain disorders.
Objective
Neurodevelopmental disorders affect millions of children in Europe and worldwide. A large body of literature indicates that inhibitory GABAergic transmission thorough Cl-permeable GABAA receptors is defective in many of these disorders. However, effective pharmaceutical treatments are still needed. There is increasing scientific evidence that varying the intracellular Cl concentration is one of the more physiological and effective ways to modulate GABAAergic transmission. This concentration is mainly established by the Cl importer NKCC1 and the Cl exporter KCC2. Importantly, the NKCC1/KCC2 ratio is defective in several brain disorders. Moreover, NKCC1 inhibition by the FDA-approved diuretic bumetanide rescues many symptoms in animal models. These findings have already led to clinical studies of bumetanide to treat a broad range of brain disorders. However, this requires chronic treatment, which poses serious issues for drug compliance, given the diuretic effect of bumetanide caused by the inhibition of the kidney-specific Cl transporter NKCC2. Crucially, these issues could be solved by selective NKCC1 inhibitors, which would have no diuretic effect. Yet there is still very little knowledge of the structure-function relationship of NKCC1 in terms of ion transportation and how bumetanide acts on NKCC1. The main goal of this fellowship is to resolve NKCC1’s structure using X-Ray crystallography and/or cryo-electron microscopy. This effort will be coupled to the functional characterization of NKCC1 using in vitro and in silico approaches. The fellow will thus integrate her research skills with key expertise in the structural and molecular biology of ion transporters, allowing her to grow into an independent group leader. Ultimately, this project will provide unprecedented insights into the structure-function relationships of NKCC1 in terms of ion transportation. This will critically accelerate the discovery of new and urgently needed drugs for brain disorders.
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 earth and related environmental sciences geology mineralogy crystallography
- natural sciences physical sciences optics microscopy
- natural sciences biological sciences molecular biology
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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.
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H2020-EU.1.3. - EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions
MAIN PROGRAMME
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H2020-EU.1.3.2. - Nurturing excellence by means of cross-border and cross-sector mobility
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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.
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.
MSCA-IF-GF - Global Fellowships
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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.
(opens in new window) H2020-MSCA-IF-2018
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Net EU financial contribution. The sum of money that the participant receives, deducted by the EU contribution to its linked third party. It considers the distribution of the EU financial contribution between direct beneficiaries of the project and other types of participants, like third-party participants.
16163 Genova
Italy
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.