UNA4CAREER
This project has received funding from the European Union’s Horizon 2020 Research and Innovation Programme under the Marie Sklodowska-Curie grant agreement Nยบ 847635.
920807. Group of Cardiovascular Pharmacology
Department of Pharmacology and Toxicology
Faculty of Medicine
We are an academic research group (http://www.labtamargo.com/) with more than 35 years of experience in the Cellular Cardiac Electrophysiology area. Importantly, we would like to stress that the hallmark of our research activity is its TRASLATIONAL nature. In fact, we form part of two collaborative research institutions funded by the Spanish Ministry of Health in which we collaborate with clinicians. Indeed, our group is a consolidate member of the Health Research Institute of the Gregorio Marañón Hospital (http://www.iisgm.com/) and also of the Spanish Virtual Network for the Cardiovascular Research (CIBERCV; https://www.cibercv.es/). Much more importantly, ten years ago our group founded, and since then coordinates, the ITACA Consortium (Investigacion Traslacional en Arritmias hereditArias) (http://itaca.edu.es/) which is financially supported by the Comunidad de Madrid. In ITACA we collaborate with the Cardiology Departments of the seven major public hospitals in Madrid that provided us with probands and families affected with inherited arrhythmias. The consortium pursues the identification of novel genes not associated with primary arrhythmogenic syndromes yet and the functional analysis of the mutations. Our final goal is to reveal unknown mechanisms responsible for the control of human cardiac electrical activity.
1) Research Supporting Centers of the University (Genomic and proteomic, microscopy or Mass spectrometry Units)
2) Common resources at our venue: ultracentrifuges, cold chamber, freezers (-40ºC and -80ºC), MilliQ water purification system, etc.
3) Resources owned by our group:
a) 6 complete set-ups for ion current and action potential recordings equipped with fluorescence microscopy;
b) a culture room with all the necessary equipment (incubators, laminar flow chamber, etc) to culture cell lines or human iPSC-derived cardiomyocytes;
c) a molecular biology laboratory with all the equipment needed for site-directed mutagenesis, PCR, Western-blotting, EMSA, luciferase assays, etc;
d) a laboratory in the Hospital Gregorio Marañón with all the necessary equipment for the isolation of human cardiac myocytes.
4) We have stable collaborations with research groups that allow us to generate transgenic mice, differentiate human iPSC into cardiomyocytes, conduct FRET/FRAP experiments, etc.
Cardiac arrhythmias are heart rhythm abnormalities that are leading causes of morbidity and mortality. They represent a therapeutic challenge since most of the currently available antiarrhythmic drugs (ADs) are inefficacious and increase mortality. ADs (except betablockers) inhibit ionic currents responsible for the electrical activity by blocking Na, Ca, and/or K channels that are present in the cardiomyocyte membrane. Paradoxically, most arrhythmias are associated with a decreased expression of ion channels. We recently demonstrated that the N-terminal domains of cardiac Na (Nav1.5) and HERG K channels produce a “chaperone-like” effect. Indeed, the N-terminal peptides of these channels, by themselves, increase the expression of Na or HERG channels, respectively. As a consequence, cardiomyocyte transfections with the cDNA encoding Nav1.5 or HERG N-terminal peptides augment the respective currents (INa and IKr). INa and IKr critically determine cardiac excitability and refractoriness and decreased excitability or prolonged refractoriness are common mechanisms responsible for arrhythmias. In this Project we pursue the design of new advanced ADs by exploiting the ability of Nav1.5 and HERG N-terminal domains to increase INa or IKr. Thus, using computational, molecular and electrophysiological experiments conducted in silico, in vitro and in vivo we aim to:
- describe the molecular mechanism and determinants responsible for the chaperone effect.
- identify the minimal molecular structure of Nav1.5 and HERG N-terminal domains that are responsible for the chaperone effect. This will allow designing the “pharmacoperones” (pharmacological chaperones) for both channels.
- to test the antiarrhythmic efficacy of these pharmacoperones in animal models of cardiac arrhythmias.
