Project description
The genetics of solute carrier transporters
To survive and maintain function, cells must closely monitor their intracellular content and import nutrients, ions, and vitamins when necessary. This takes place through the solute carrier (SLC) superfamily of transporter proteins, which are located in the membrane of most organelles, including the plasma membrane. Given that SLCs are implicated in disease and may serve as therapeutic targets, there is a need to understand more about their biology and function. The EU funded REsolution project will capitalise on the knowledge generated during its predecessor project RESOLUTE on SLC biology and biochemistry. During REsolution, researchers will focus on SLC genetics and unveil the impact of genetic variation on function, offering important information for the design of novel drugs.
Objective
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 actionCoordinator
1090 Wien
Austria