Descripción del proyecto
La genética de los transportadores de portadores de solutos
Para sobrevivir y conservar su funcionalidad, las células deben vigilar atentamente su contenido intracelular y, cuando resulte necesario, importar nutrientes, iones y vitaminas. Para ello utilizan la superfamilia de portadores de solutos de las proteínas transportadoras que se encuentran en la membrana de la mayoría de los orgánulos, incluida la membrana plasmática. Dado que los portadores de solutos participan en la enfermedad y pueden servir como dianas terapéuticas, debemos comprender mejor su biología y función. El proyecto REsolution, financiado con fondos europeos, aprovechará los conocimientos obtenidos por su predecesor, el proyecto RESOLUTE, sobre la bioquímica y la biología de los portadores de solutos. Durante REsolution, los investigadores se centrarán en la genética de los portadores de solutos y aclararán el impacto de la variación genética sobre su funcionamiento, con lo que brindarán información de gran importancia para el diseño de nuevos fármacos.
Objetivo
Solute carriers (SLCs) are the largest family of membrane transporters encoded in the human genome and their role in trafficking nutrients, ions, vitamins and cofactors is vital for maintaining homeostasis in individual cells, organs and tissues. Their misfunction is associated with a variety of diseases and a small number of individual SLCs are successful drug targets. Despite their importance, SLCs remain understudied and a surprisingly large proportion is deemed “orphan” in terms of transport function. The ongoing RESOLUTE IMI consortium is working on the systematic de-orphanization of SLCs and is highly successful in creating open-access tools, high-throughput assays and omics data. This effort is focused on basic aspects of SLC biochemistry and biology and was not meant to include the medical dimension. In the REsolution program we propose here, we exploit the unique opportunity to now link the RESOLUTE knowledge to physiology and disease through human genetics. The goal is to maximize the chances that SLC transporters will become successful drug targets and use the growing amount of data becoming available on genetic variations and disease association to assign pathophysiological relevance to individual transporters. Concretely, we plan to: 1) assemble human SLC genetic information and annotate within the RESOLUTE knowledgebase; 2) study the structure-activity relationship for selected SLC variants, 3) use deep mutagenesis and artificial intelligence to develop the equivalent of a “Rosetta stone” allowing the interpretation of SLC genetic variation. This will allow us to not only contextualize SLCs, as elucidated by RESOLUTE, in the current human medical genetics landscape, but also to create an SLC prioritization rationale and a resource of the whole SLC family for the pharmaceutical industry valid for years to come.
Ámbito científico
Palabras clave
Programa(s)
Tema(s)
Convocatoria de propuestas
H2020-JTI-IMI2-2020-22-single-stage
Consulte otros proyectos de esta convocatoriaRégimen de financiación
RIA - Research and Innovation actionCoordinador
1090 Wien
Austria