General summary. The present project aims to comprehensively investigate physiological responses to altitude/hypoxia during rest and exercise in prematurely born, but otherwise healthy adults. Specifically, we aim to elucidate the underlying mechanisms of the altered resting and exercise cardiovascular, respiratory, cerebral and hematological responses to hypoxia in prematurely born individuals. The obtained results from this cohort will be compared to the data from two control groups consisting of 1) healthy, age and aerobic capacity-matched individuals born at full-term and 2) individuals with persistence of fetal circulation after birth, known to exhibit exaggerated hypoxic pulmonary hypertension. While acute hypoxic effects will be the focus of the project’s first phase we will test the effect of prolonged terrestrial (real) or simulated (normobaric hypoxia) altitude exposures in the second part. This phase will, in addition to the insight into the prolonged altitude acclimatization modulation in prematurely born individuals, also enable us to investigate the potential differences between the effects of normobaric (simulated) and hypobaric (terrestrial) hypoxia in this cohort. Collectively, the project aims to address the following main research questions: 1. Does exposure to hypoxia at rest exert greater physiological strain for individuals born prematurely as compared to individuals born at full-term (and why)? 2. Does exercise performed in hypoxia exert greater physiological strain for individuals born prematurely as compared to individuals born at full-term (and why)? 3. Do pre-term individuals exhibit similar physiological responses to hypoxia as those with persistence of fetal circulation after birth (and why)? 4. Is physical capacity in hypoxia reduced to a greater degree in individuals born prematurely as compared to individuals born at full-term? 5. Do pre-term individuals exhibit similar physiological responses to full-term born healthy individuals during both acute and prolonged exposures? 6. Are the physiological effects of simulated (normobaric) and terrestrial (hypobaric) altitude comparable in a cohort of prematurely born individuals? Scientific novelty and applied value. The proposed project will be the first to investigate the effects of prolonged high-altitude exposure on acclimatization ability of prematurely born individuals. Moreover, the data obtained from both stages of the project will enable evidence-based recommendations for prolonged high-altitude sojourns for individuals born prematurely. The obtained results will also provide extensive physiological database regarding the development of cardiorespiratory control in individuals born prematurely. Finally, the obtained comparison data between normobaric and hypobaric hypoxia will be unique and will scrutinize the relevance of the current diagnostic tests for patho-physiological responses to high-altitude which are normally conducted in normobaric hypoxic condition. Especially, since no study to date compared these effects performed in clinical cohorts. Project team and feasibility. Collectively, the project team consist of world-renown experts within the field of hypoxia and altitude physiology, respiratory and cardiovascular physiology control as well as biochemistry of redox balance. Importantly, it combines individuals with expertise and extensive experience in both basic, applied and clinical research work. The up-to-date research program of the project group clearly indicates the feasibility and added value of the proposed project since numerous studies involving both acute and prolonged hypoxic acclimation protocols and incorporating the proposed experimental methods have already been successfully executed and their outcomes subsequently published in prestigious international clinical & applied scientific journals. Finally, the previous to-date collaboration of all project partners further ensures that the project is feasible and will be executed and disseminated in a high-quality manner. Finally, similar project proposal (comprising the same project partners) has previously been submitted for funding to the Horizon 2020 and, albeit not being funded, has been awarded the Seal of Excellence - a quality label awarded to project proposals submitted to EU's research and innovation funding programme, that were judged to deserve funding but did not get it due to budget limits.