Description du projet
Accélérer la découverte de médicaments pour les maladies du cerveau
L’importateur de chlorure (Cl) NKCC1 et l’exportateur de Cl KCC2 contribuent à la régulation de la concentration en chlorure dans les neurones. Un déséquilibre entre eux semble être à l’origine de nombreuses maladies neurologiques, notamment plusieurs maladies du cerveau. En outre, l’inhibition du NKCC1 par le bumétanide, un diurétique approuvé par la FDA, permet d’atténuer de nombreux symptômes dans des modèles animaux. Cette option thérapeutique exige un traitement chronique, ce qui pose des problèmes cruciaux en matière de prise du médicament, étant donné l’effet diurétique du bumétanide causé par l’inhibition du transporteur de Cl propre au rein, le NKCC2. Dans ce contexte, le projet 3D NKCC1, financé par l’UE, apportera un nouvel éclairage sur les relations structure-fonction du NKCC1 en termes de transport ionique. Les résultats donneront un grand coup d’accélérateur à la découverte de médicaments nouveaux et indispensables destinés au traitement des maladies du cerveau.
Objectif
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.
Champ scientifique
Programme(s)
Régime de financement
MSCA-IF-GF - Global FellowshipsCoordinateur
16163 Genova
Italie