Projektbeschreibung
Beschleunigung der Wirkstoffforschung zu Hirnerkrankungen
Der Chlorid-Importeur (CI) NKCC1 und der CI-Exporteur KCC2 unterstützen die Regulierung der neuronalen Chloridkonzentration. Ein gestörtes Verhältnis scheint hinter vielen neurologischen Erkrankungen, wie schweren Hirnerkrankungen, zu stecken. Außerdem lindert die NKCC1-Hemmung durch das von der FDA zugelassene diuretische Bumetanid viele Symptome in Tiermodellen. Doch dafür ist eine chronische Behandlung notwendig, die aufgrund der harntreibenden Wirkung von Bumetanid, die durch die Hemmung des nierenspezifischen CI-Trägers NKCC2 ausgelöst wird, große Probleme für die Medikamenten-Compliance darstellt. Vor diesem Hintergrund wird das EU-finanzierte Projekt 3D NKCC1 Erkenntnisse über die Struktur-Funktions-Verbindung von NKCC1 hinsichtlich des Eisentransports liefern. Die Ergebnisse werden die Forschung zu neuen und dringend benötigten Wirkstoffen für Hirnerkrankungen deutlich beschleunigen.
Ziel
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.
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MSCA-IF-GF - Global FellowshipsKoordinator
16163 Genova
Italien