Projektbeschreibung
Genetische Analysen von SLC-Transportproteinen
Für den Erhalt von Zellfunktionen und Überlebensfähigkeit müssen Zellen den intrazellulären Nährstoff-, Ionen- und Vitamingehalt genau überwachen und diese Stoffe bei Bedarf zuführen. Dies geschieht durch die Transportproteine der SLC-Superfamilie (solute carrier), die in den Membranen der meisten Organellen, u. a. der Plasmamembran, lokalisiert ist. Da diese Transportproteine für die Entstehung von Krankheiten relevant und somit therapeutische Ziele sind, muss deren Biologie und Funktion genauer erforscht werden. Das EU-finanzierte Projekt REsolution baut auf dem Vorgängerprojekt RESOLUTE zur Biologie und Biochemie von SLC auf. Schwerpunkt von REsolution sind genetische Aspekte von SLC und Effekte genetischer Variation auf deren Funktion, um die Forschung zu neuen Arzneimitteln zu befördern.
Ziel
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.
Wissenschaftliches Gebiet
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Aufforderung zur Vorschlagseinreichung
H2020-JTI-IMI2-2020-22-single-stage
Andere Projekte für diesen Aufruf anzeigenFinanzierungsplan
RIA - Research and Innovation actionKoordinator
1090 Wien
Österreich