Description du projet
La génétique des transporteurs de solutés
Pour survivre et maintenir leurs fonctions, les cellules doivent surveiller attentivement leur contenu intracellulaire et importer des nutriments, des ions et des vitamines, lorsque cela s’avère nécessaire. Cette importation a lieu par le biais de la superfamille des transporteurs de solutés (SLC), des protéines présentes dans la membrane de la plupart des organites, notamment la membrane plasmique. Étant donné que les SLC sont associés à des maladies et peuvent servir de cibles thérapeutiques, il importe de mieux comprendre leur biologie et leur fonction. Le projet REsolution, financé par l’UE, s’appuiera sur les connaissances générées par son prédécesseur, le projet RESOLUTE, en matière de biologie et de biochimie des SLC. Dans le cadre de REsolution, les chercheurs s’intéresseront à la génétique des SLC et dévoileront l’incidence de la variation génétique sur la fonction cellulaire, ce qui génèrera de précieuses informations pour la conception de nouveaux médicaments.
Objectif
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.
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RIA - Research and Innovation actionCoordinateur
1090 Wien
Autriche