Oxygen sensing and disease Laboratory

The HIF oxygen sensing molecular machinery in cardiorespiratory diseases

O2 supply to cells or tissues becomes limited during the development of numerous pathological scenarios such cardiac ischemia, inflammation or expansion of white adipose tissue. Cells respond to these O2 fluctuations by activating the hypoxia-inducible factors HIF-1α, HIF-2α. In our research group we aim to study the in vivo contribution of these factors in pathology. We have developed the necessary technology to inactivate in adult mice HIF-1α or HIF-2α (loss of function models) as well as their main repressor VHL leading to a constitutive activation of both HIFs (gain of function model) in order to study the role of HIFs in tumour development (Elorza et al. 2012 Molecular Cell), lung disease (Torres-Capelli et al. 2016 Scientific Reports) or metabolism (Soro et al. 2016, Cell Reports). Here we propose to evaluate the role HIF-1α or HIF-2α in lung responses to low oxygen tension and their therapeutical role in preclinical models of chronic obstructive pulmonary disease (COPD) and its clinical and diagnostic role in COPD patients. Moreover, we have recently identified novel HIF targets genes that promote cytoprotection in hypoxic conditions. Therefore we also aim to evaluate its role in myocardium tolerance in ischemia reperfusion settings using cardiac specific gene inactivation of these target genes (mice available). Collectively, our project combine mouse knock-out technology and clinical data to identify novel therapeutic opportunities in cardiorespiratory diseases by exploiting HIF signalling pathways in vivo.