Descripción del proyecto
Descubrimiento acelerado de fármacos para las encefalopatías
El importador de cloruro NKCC2 y el exportador de cloruro KCC2 contribuyen a regular la concentración de cloruro. Una proporción inadecuada podría ser la causa de muchas enfermedades neurológicas y varias encefalopatías. Es más, la inhibición de NKCC1 por la bumetanida, diurético aprobado por la Administración de Medicamentos y Alimentos de los Estados Unidos, alivia muchos síntomas en modelos animales. No obstante, el tratamiento es crónico, lo que implica varios problemas de cumplimiento terapéutico, sobre todo dado el efecto diurético de la bumetanida provocado por la inhibición del transportador de cloro específico del riñón NKCC2. Dado todo lo anterior, el proyecto financiado con fondos europeos 3D NKCC1 generará información sobre las relaciones entre función y estructura del NKCC1 en lo tocante al transporte de iones. Sus resultados acelerarán el descubrimiento de fármacos nuevos y muy necesarios para las encefalopatías.
Objetivo
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.
Ámbito científico
Programa(s)
Régimen de financiación
MSCA-IF-GF - Global FellowshipsCoordinador
16163 Genova
Italia