Cód. SSPA: IBiS-B-06
The research carried out by our group focuses on the basic mechanisms underlying oxygen (O2) sensing by cells and their responses to hypoxia (low O2 tension).
Hypoxia is a critical factor in the pathogenesis of numerous common causes of human morbidity and mortality. Knowledge of the molecular mechanisms involved in cellular transcriptional responses to sustained hypoxia has progressed enormously and research advances have had an outstanding impact in several fields of medicine. However, despite their obvious biomedical relevance, the molecular basis of acute cellular O2 sensing and the systemic adaptations to hypoxia have remained elusive for decades.
Our group investigates the nature of the sensors and effectors that mediate acute responses to hypoxia, especially in the carotid body chemoreceptor cells and arterial smooth muscle. In parallel with this main research project, we work on the potential role of endogenous neurotrophic factors in the pathogenesis and therapy of Parkinson disease. We are also interested in the contribution of mitochondrial metabolism and bioenergetics to neurogenesis as well as to neuronal homeostasis.
Research lines
- Cellular mechanisms of acute oxygen sensing
Acute O2 sensing by specialized chemoreceptor cells is necessary for the activation of rapid, life-saving cardiorespiratory reflexes that minimize the deleterious effect of hypoxia. The prototypical acute O2 sensing organ is the carotid body, a highly irrigated structure located in the carotid bifurcation that contains neuron-like chemoreceptor glomus cells that, upon activation, elicit hyperventilation and sympathetic activation to favor adaptation to hypoxia. Our studies in this organ have provided an experimentally robust conceptual framework that has advanced the molecular definition of acute O2 sensing. We have shown that carotid body glomus cells contain specialized mitochondria which are O2 sensors that generate signals (NADH and ROS) that regulate membrane ion channel activity and transmitter release. The unique sensitivity of glomus cell mitochondria to physiologically relevant changes in O2 tension is due to their specialized metabolism and depends on the integrated action of specific transcription factors, enzymes and components of the mitochondrial electron transport chain.
Currently, the group is trying to complete the characterization of the molecular mechanisms of acute O2 sensing by arterial chemoreceptors, to determine whether these mechanisms can be generalized to other cell types acutely responding to hypoxia, and to identify novel pharmacological targets for the therapy of respiratory depression or sympathetic overactivation. Within this line of work, we are also carrying out studies on the plasticity of arterial chemoreceptors during chronic intermittent hypoxia, a frequent scenario in patients with sleep apnea.
- Neurodegeneration and neuroprotection in Parkinson disease
The objective of this research area is to elucidate the physiological role of endogenous GDNF (glial cell line-derived neurotrophic factor) on central catecholaminergic neurons. Our goal is to identify the signaling pathways that modulate endogenous GDNF production and to identify potential pharmacological targets for a neuroprotective therapy in Parkinson disease.
- Influence of oxidative metabolism on neurogenesis and neuronal homeostasis
The generation of neurons (neurogenesis) is essential for brain development and function, and relies on the activity of neural stem cells. In recent years our group has worked on the involvement of the mitochondrial metabolism in neural stem cell activity. Elucidation of the mechanisms orchestrating brain formation may contribute to get a better understanding of the pathogenesis and treatment of complex neurological disorders. Understanding the role of mitochondria in neuronal homeostasis may also help preventing neurodegeneration and the recovery of neuronal damage after ischemia.
