Descrizione del progetto
La genetica dei portatori di soluto
Per sopravvivere e mantenere le capacità funzionali, le cellule devono controllare attentamente il proprio contenuto intracellulare e importare all’occorrenza sostanze nutritive, ioni e vitamine. Ciò avviene tramite la superfamiglia dei portatori di soluto delle proteine di trasporto, che è situata nella membrana della maggior parte degli organuli, tra cui la membrana plasmatica. Considerato che tali proteine sono coinvolte nella malattia e possono fungere da bersagli terapeutici, è fondamentale capire di più circa la loro biologia e funzione. Il progetto REsolution, finanziato dall’UE, sfrutterà le conoscenze sulla biologia e sulla biochimica di tale gruppo generate durante il suo progetto predecessore RESOLUTE. Durante REsolution, i ricercatori concentreranno l’attenzione sulla genetica dei portatori di soluto e scopriranno l’impatto della variazione genetica sulle funzionalità, fornendo informazioni importanti per la progettazione di nuovi farmaci.
Obiettivo
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.
Campo scientifico
Parole chiave
Programma(i)
Argomento(i)
Invito a presentare proposte
H2020-JTI-IMI2-2020-22-single-stage
Vedi altri progetti per questo bandoMeccanismo di finanziamento
RIA - Research and Innovation actionCoordinatore
1090 Wien
Austria