Anaemia is the most common pathological condition affecting 1.6 billion individuals worldwide. It thus presents a serious health care problem and an economic burden. Reduction in red blood cell (RBC) number can be caused by blood loss, diet, stress conditions including endurance sport, and pathologies which are caused by primary genetic aberrations or are secondary to the malfunction of other cell types. Transfusion of RBC, which is often the only cure for severe cases of anaemia, is associated with risks such as thrombosis and transfusion reactions due to allo-immunisation. There is an unmet need to improve treatment of anaemia through early and accurate diagnosis, targeted treatment, and increased safety and effectiveness of RBC transfusion. The aim of RELEVANCE is to improve fast and cost-effective diagnosis of the underlying cause of primary anaemia, and to improve treatment options for both general and personalised medicine. We defined five key objectives: (1) to improve diagnostics of anaemia, particularly for hereditary rare forms of anaemia (RA); (2) to find novel treatments for anaemia that target RBC production, ageing and clearance; (3) to reduce premature loss of RBC following transfusion; (4) to produce cultured RBC for transfusion; (5) to monitor and optimise RBC function during sport and exercise. RELEVANCE will train 15 early stage researchers (ESR) at four SMEs and eight academic partners, two of whom are at blood supply centres and two are diagnostic centres for RA. The continuous interactions between the clinic, blood supply centers, basic research, and industry will select for the most relevant unmet medical needs, and will stimulate innovative procedures that are immediately probed for applicability and validity both in a research and a clinical setting. RELEVANCE will organize three open access summer schools, extending training beyond the ESR of the ITN sustaining the critical number of young talented professionals in the field.

Drug transporters, such as the Breast Cancer Resistance Protein (ABCG2), are recognized as key players in the distribution of drugs in human. The localization of this efflux pump in organs responsible for drug biotransformation and excretion gives ABCG2 an important gatekeeper function in controlling drug access to metabolizing enzymes and excretory pathways. ABCG2 is also found in cancer cells, where it mediates the extrusion of drug to the cell's exterior. In doing so, it prevents entry of anticancer drugs into cells and, hence, impairs the chemotherapeutic treatment of this life-threatening disease. In this proposal, we will study fundamental aspects of the transport mechanism of human ABCG2. In particular, we will study the previously unknown ability of ABCG2 to transport ions such as protons. We are interested to learn which ions are transported (in addition to protons, for example sodium, potassium, chloride ions), how ABCG2 transports these ions, and why? What is the relationship between ion transport and drug transport? ABCG2 is thought to be active as a dimer, which we will test by mass spectrometry, and is likely to have drug binding sites that are alternately exposed to the inside surface of the membrane (where drugs bind) and outside surface of the membrane (where drugs are released). Based on the available crystal structures of multidrug binding proteins (transporters and transcriptional regulators), we hypothesize that (i) protons and other ions might displace drugs from binding sites in ABCG2 during drug release and/or (ii) their binding might support structural changes in the two ABCG2 units and their interface, that are associated with the reorientation of the drug binding sites. Fundamental knowledge about ABCG2 activity will allow the rational development of inhibitors (also termed modulators) of this efflux pump that could be used to target drugs to specific parts of the human body, and to improve chemotherapy of cancers.