I completed my PhD in 2017 (cum laude) in the laboratory of Prof. Maria Teresa Miras-Portugal at the University Complutense Madrid. The main objective of my PhD was to study the role of the vesicular nucleotide transporter, VNUT, in developmental and differentiation processes of neural tissues. Once I finished my PhD, I continued studying the lineage progression of cerebellar progenitors and the role of VNUT in this process. After that, I worked as Associated Lecturer in the Department of Basic Biomedical Sciences of the European University of Madrid. In October 2019, I was awarded a Marie-Skłodowska Curie Individual Fellowship at the Royal College of Surgeons (RCSI, Dublin, Ireland). This project (NeoPur 844956), under the supervision of Dr Tobias Engel, is focused on the establishment of P2X7-targeting as novel treatment strategy for seizures in neonates and identify novel diagnostic test for neonatal seizures based on purinergic signaling.
The neonatal period is the most vulnerable time for the occurrence of seizures following brain injury with an incidence of 3-5 every 1,000 births. The high risk of developing seizures is because the neonatal brain is characterized by an increased excitability state due to the developmental unbalance between excitatory and inhibitory neural pathways, necessary for the correct formation of the brain. The most common cause of neonatal seizures is hypoxic-ischemic events which occur during birth and carry with them a risk of long-term epilepsy and neurological and cognitive deficits. As a result, seizures in neonates are recognized as a medical emergency and require rapid treatment. Currently, the techniques used to diagnose neonatal seizures have a high proportion of misdiagnosis resulting in over-treatment (about 50% of cases). The main treatments for neonates include hypothermia and the first line drug is phenobarbital, which exhibit low responses rates, and, in addition, may lead to neurological deficits in later life. Consequently, there is a pressing need to identify reliable markers to better diagnose and to develop new treatments with higher response rates without affecting the normal development of the brain.
Purines are extracellular signalling molecules which act as neurotransmitter and neuromodulators, and they can be released during pathological conditions in the brain, including seizures and inflammation. Moreover, purines are present in body fluids of humans and rodents and can be detected with a minimally invasive procedure (e.g. blood). These features of purines make them very attractive biomarkers for diagnostic of disorders of the CNS.
Previous works have demonstrated the clear causal role for P2X7 signalling during seizures and epilepsy. Moreover, the use of P2X7 antagonists was shown to reduce seizure severity during acute seizures and to protect the brain from cell death. Recently, data from a model of hypoxia-induced seizures in neonates suggest a role for P2X7 during early-life seizures, in which P2X7 expression increases following seizures and pre-treatment with P2X7 antagonists reduces seizure severity.
Therefore, our overall research aim is to establish P2X7-targeting as novel treatment strategy for seizures in neonates and identify novel diagnostics for neonate seizures based on purinergic signalling.
“Physiopathological Role of the Vesicular Nucleotide Transporter (VNUT) in the Central Nervous System: Relevance of the Vesicular Nucleotide Release as a Potential Therapeutic Target” Miras-Portugal MT., Menéndez-Méndez A., Gómez-Villafuertes R., Ortega F., Delicado EG., Pérez-Sen R., Gualix J. Frontiers in Cellular Neuroscience, 2019 May 17;13:224. doi: 10.3389/fncel.2019.00224. Link to paper here.
“Specific Temporal Distribution and Subcellular Localization of a Functional Vesicular Nucleotide Transporter (VNUT) in Cerebellar Granule Neurons” Menéndez-Méndez A., Díaz-Hernández J.I., Ortega F., Gualix J., Gómez-Villafuertes R. and Miras-Portugal MT Frontiers in Pharmacology, 2017 Dec 8:951. doi: 10.3389/fphar.2017.00951. Link to paper here.
“Live Imaging Followed by Single Cell Tracking to Monitor Cell Biology and the Lineage Progression of Multiple Neural Populations” Gomez-Villafuertes R., Paniagua-Herranz L., Gascón S., de Agustín-Durán D., de la O Ferreras M., Gil-Redondo J.C., Queipo M.J., Menéndez-Méndez A., Pérez-Sen R., G Delicado E., Gualix J., R Costa M., Schroeder T., Miras-Portugal MT, Ortega F. Journal of Visualize Experiments (JoVE). (130), e56291, doi: 10.3791/56291 (2017). Link to paper here.
“MiR-125a-3p timely inhibits oligodendroglial maturation and is pathologically up-regulated in human multiple sclerosis” Lecca, D., Marangon, D., Coppolino, G.T., Menéndez-Méndez A., Finardi A., Costa G.D., Martinelli V., Furlan R., Abbracchio M.P. Scientific Reports, 2016 Oct; 6:34503. Link to paper here.
“The vesicular nucleotide transporter, VNUT, is involved in the extracellular ATP effect on neuronal differentiation” Menéndez-Méndez, A., Díaz-Hernández, J.I. and Miras-Portugal M.T. Purinergic Signalling, 2015 Jun, 11(2):239-49T. Link to paper here.