Erythrocytes represent an estimated 84% of all cells in the human body. During circulation, they experience a huge variety of physical and chemical stimulations, such as pressure, shear stress, hormones or osmolarity changes. These signals are translated into cellular responses through ion channels that modulate erythrocyte function. Ion channels in erythrocytes have only recently been recognised as the utmost important players in physiology and pathophysiology. Despite this awareness, their signalling, interactions and concerted regulation, such as the generation and effects of 'pseudo action potentials', remain elusive. INNOVATION proposes a systematic, conjoined approach using molecular biology, in vitro erythropoiesis, state-of-the-art electrophysiological techniques, methods to detect erythrocyte functionality and patient samples (channelopathies and other red blood cell-related diseases) to decipher and make use of ion channel functions in terms of disease treatment concepts. We need to overcome the challenges that hinder the gain of knowledge within the field, using genetic manipulation of progenitors, cell differentiation into erythrocytes, statistically efficient electrophysiological recordings of ion channel activity that are limited by the heterogeneity of the cell population (120 days of lifespan without any protein renewal) or access to large cohorts of patients. Our multidisciplinary team includes biophysicists and cell biologists to investigate erythrocyte characteristics and bioengineers to develop diagnostic devices. INNOVATION involves academic research centres as well as diagnostic labs providing patient samples, blood bank research centres developing cultured transfusion products and SMEs that provide and develop diagnostic tools or innovative therapeutic red blood cell products. The consortium offers on-site training, secondments and a variety of courses in transferrable and complementary skills to 10 doctoral candidates.

After exiting the bone marrow, reticulocytes mature to form red blood cells (RBCs) which are highly adapted cells Red blood cells (RBCs) travel through our circulation during their entire lifetime of in average 120 days. This means they are in constant move and adapt to their surrounding by shape changes, e.g., when in high speed flow or with even more severe volume adaptations, when they squeeze through small capillaries or the slits of the spleen having less than half their own size. While on the move, RBCs have to deal with continuous changes in oxygen tension and pH, have to scavenge reactive oxygen species, and need to balance their responses towards the chemical and mechanical challenges. In contrast, most of the knowledge we gained about RBCs as well as diagnostic methods rely on RBCs in relative stasis, such as flux measurements, conventional patch-clamp, calorimetric assays, density centrifugation, atomic force microscopy, just to name a few. In the most extreme conditions the cells of investigation are even dead like in blood smears, electron microscopy or cyto-spins. Even if cells are on the move like in flow cytometers, they may rest in a drop of liquid. Furthermore, when taken from the circulation, the flow of the RBCs is suddenly terminated and (together with the application of anticoagulants) they experience a completely different environment that is likely to impair their properties. The objective of EVIDENCE is the exploration of the properties and behaviour of RBCs under flow conditions and in vivo to understand pathophysiology and to design novel diagnostic devices. Theoretical models will help to understand these RBC properties and will enable the transfer of the gained knowledge into diagnostic devises in general and into the development of a spleen-on-the-chip in particular. Furthermore we aim to understand the effect of the flow in bioreactors, allowing the efficient production of RBCs in vitro with the goal to produce RBC for transfusion.

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.