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Regulation of red cell life-span, erythropoiesis, survival, senescence and clearance

Periodic Reporting for period 2 - RELEVANCE (Regulation of red cell life-span, erythropoiesis, survival, senescence and clearance)

Reporting period: 2017-09-01 to 2019-11-30

Red blood cells are the most abundant cell type in our body making up more than 60% of all cells. Their major task is to provide efficient gas exchange, delivering oxygen to and removing CO2 from the tissues. However, in addition they control vascular tone, combat oxidative stress and sense multiple signals of stress and disease. Over 1.5 billion people world-wide experience pathological condition associated with red blood cell deficiency, known as anemia. Our ITN RELEVANCE brought together 13 partners in various areas of red blood cell research and clinical hematology as well as industrial partners producing software and devices to understand the molecular mechanisms of processes running in healthy and diseased erythroid precursor cells in bone marrow, circulating and stored red blood cells. This unique team of experts from nine European countries was aiming to train 15 ESRs to become “the next generation” of professionals in the coming world of personalised medicine and modern translational research and diagnostic device development. Our ESRs feel comfortable in the international multidisciplinary environment and are integrated into the groups of world-class experts in the field when solving rather demanding research, clinical and engineering problems together. Within the project novel approaches (gene arrays and new application and protocols to use for hematological applications of the existing devices) and device prototypes were developed for diagnosis and monitoring of the disease severity and efficacy of therapies. These new diagnostic approaches analyse properties of individual cells and their responses to stress and are, therefore, radically different from the one currently used in the clinical labs, and more powerful as well. Some of the prototypes are already tested in clinical settings due to the successful networking between the clinical and industrial partners. Progress has been made in understanding of the underlying causes of primary anaemia and in defining the markers of disease severity. New optimised protocols were developed for in vitro red blood cell production. Knowledge of the molecular mechanisms of erythropoiesis, aging and clearance of circulating red blood cells was extended for the erythroid cell cultures and for humans ascending to the high altitude, adapting to hypobaric hypoxia and moving back to the sea level. Responses of human red blood cells to erythropoietin stimulation were observed and molecular mechanisms of those are being unravelled. Finally, handling of calcium ions was identified as one of the key factors in adaptation to endurance training and in development of pathology.
The achievements within the project are of societal importance. They enable better diagnosis and treatment of patients with rare anemias. Novel technical advances and new blood testing approaches emerging during the project contribute to the innovation and technological development within the EU. Finally, young specialists that were trained within the consortium are our contribution to the future medicine, research and industrial enterprises.
Work of partners within the RELEVANCE consortium was structured within five scientific work packages (WPs), and progress was achieved in each of them. One main result is the generation of intellectual property and new technologies that can revolutionize the work of clinical labs by improving their diagnostic potential to identify the optimal strategies for treatment of individual patients and to monitor responsiveness of each patient to the therapy. Partners of the RELEVANCE consortium developed new device prototypes and tests involving already existing machines to enable diagnosis and monitoring of progression of disease manifestation and efficacy of therapies. New software involving artificial intelligence was produced for recognition of red blood cell shapes and association of the obtained results were shown to have high predictive and diagnostic power. These technologies were tested in clinical settings, also during the ongoing clinical trial, in which a new therapy developed by one of the partners is used for treatment of sickle cell disease patients.
Another important result is the development of gene arrays to identify mutations that are often identified as primary causes of rare anemias. However, diversity in disease manifestation and responsiveness of patients to therapies require novel functional approaches, in which properties of individual red blood cells are analyzed in stasis or under stress conditions.
Partners of the RELEVANCE consortium made substantial progress in optimizing the technologies for production of red blood cells in bioreactor settings to improve the outcome of blood transfusions. Knowledge has been gained for the mechanisms of red blood cell clearance and interaction with endothelial cells and spleen components, factors in control of clearance and turnover rate of red blood cells of patients and healthy people exposed to high altitude or practicing endurance exercises.
Synergistic effects achieved from the interdisciplinary projects running within the consortium can be clearly seen from the amount of information that was obtained by each participant profiting from access to infrastructure and from the know-how of the other partners. Early stage researchers on the project profited even more from this most efficient networking: They were able to be seconded to partner-groups (labs, clinics, SMEs) and were exposed to different points of view and approaches to solve the same problem. As a result, they are the ones that may now use the new technologies, improving them further within the SMEs and introducing them to the clinical hematologists. These 15 young specialists were presenting their achievements to the world-leading experts in red cell research during international meetings and were acknowledged as the next generation of specialists world-wide. Their career development is boosted, and they know what they want to do. Within the project a European network of experts was formed with very strong connections and dedication to find further funding for interactive projects. The achievements of this network laid a solid basis of dominance of the European research community in the field, which was acknowledged during the meeting of European Red Cell Society in Ascona, Switzerland in March 2019. Joint efforts facilitated development of intellectual property resulting in patent filing by the SME partners. Finally, the end-users of our advanced understanding of processes occurring in red blood cells are healthy people practicing endurance exercises or spending some time at high altitude as well as patients diagnosed with anemia, who are able to get access to the most effective and best modern therapy.