Objective Oxygen (O2) is essential for life on Earth. This proposal deals with the study of the molecular mechanisms underlying acute O2 sensing by cells, a long-standing issue that is yet to be elucidated. In recent years, the discovery of hypoxia inducible transcription factors and their regulation by the O2-dependent hydroxylases has provided a solid framework for understanding genetic responses to sustained (chronic) hypoxia. However the mechanisms of acute O2 sensing, necessary for the activation of rapid, life-saving, compensatory respiratory and cardiovascular reflexes (e.g. hyperventilation and sympathetic activation), are unknown. While the primary goal of the project is to characterize the molecular mechanisms underlying acute O2 sensing by arterial chemoreceptors (carotid body –CB- and adrenal medulla –AM-), we will also extend our study to other organs (e.g. pulmonary and systemic arteries) of the homeostatic acute O2-sensing system. We will investigate the role of mitochondria, in particular complex I (MCI), in acute O2 sensing. Previous data from our group demonstrated that rotenone, a MCI blocker, selectively occludes responsiveness to hypoxia in CB cells. In addition, our unpublished data indicate that sensitivity to hypoxia (but not to other stimuli) is lost in mice with genetic disruption of MCI genes in CB and AM cells. We have shown that the adult CB is a plastic organ that contains a population of multipotent neural stem cells. Hence, another objective of the project is to study the role of these stem cells in CB modulation (over- or infra-activation), which may participate in the pathogenesis of diseases. In the past, our group has made seminal contributions to unveiling the cellular bases of arterial chemoreception. The discovery of stem cells in the CB and the generation of new genetically modified mouse models, put us in a leading position to elucidate the molecular bases of acute O2 sensing and their biomedical implications. Fields of science engineering and technologymaterials engineeringfibersnatural sciencesbiological sciencescell biologycell metabolismmedical and health sciencesmedical biotechnologycells technologiesstem cellsnatural sciencesbiological scienceszoologymammalogymedical and health sciencesbasic medicinephysiologyhomeostasis Programme(s) H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC) Main Programme Topic(s) ERC-ADG-2014 - ERC Advanced Grant Call for proposal ERC-2014-ADG See other projects for this call Funding Scheme ERC-ADG - Advanced Grant Host institution UNIVERSIDAD DE SEVILLA Net EU contribution € 2 843 750,00 Address CALLE S. FERNANDO 4 41004 Sevilla Spain See on map Region Sur Andalucía Sevilla Activity type Higher or Secondary Education Establishments Links Contact the organisation Opens in new window Website Opens in new window Participation in EU R&I programmes Opens in new window HORIZON collaboration network Opens in new window Total cost € 2 843 750,00 Beneficiaries (1) Sort alphabetically Sort by Net EU contribution Expand all Collapse all UNIVERSIDAD DE SEVILLA Spain Net EU contribution € 2 843 750,00 Address CALLE S. FERNANDO 4 41004 Sevilla See on map Region Sur Andalucía Sevilla Activity type Higher or Secondary Education Establishments Links Contact the organisation Opens in new window Website Opens in new window Participation in EU R&I programmes Opens in new window HORIZON collaboration network Opens in new window Total cost € 2 843 750,00