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Development and application ol atrial myocyte models to investígate mechanisms that conter patients a high risk of atrial fibrillation

Total activity: 1
Type of activity
Competitive project
Funding entity
Funding entity code
36.300,00 €
Start date
End date
Atrial fibrillation is an importan! economic burden on the health care system, but the complex pathophysiology combined with its self­
perpetuating nature has so far hampered etficient treatment of this continuously growing disease. One of the main issues that remains to be resolved is the genetic bases of AF, which remain elusive. Only rare mutations accounting for a small fraclion of patients with familia! AF have been associated to changes in the function of different ion channels. as for instance the variants on 4q25 or 1q21. Therefore, a successful identification of common genetic risk variants w th a high risk of AF in this proposal could mean a break-through far risk
stratification, early detection of patients with high risk of developing AF, and for the identification of selective pharmacological targets linked to high risk variants. The main goal is to identify !he molecular and cellular electrophysiological profile of atrial myocytes from patients with common genetic polymorphisms associated with atrial fibrillalion in order to identify the variants and the underlying mechanisms that confer a high risk lor this arrhythmía on carriers of these variants.
To further explore the role of these mechanisms we shall use mathematical models of single and multicellular atrial myocyte models. The single cell models allow investigation of the risk that a changa in a single molecular mechanism imposes on myocyte function (which is impossible to determine in isolated myocytes because ali mechanisms are interconnected and cannot be separated out). Additionally, the mathematical models shall be used to determine how other mechanisms known to increase risk fer arrhythmia such as cellular
hypethrophy, atrial dilation and mechanical stress.
Thus, we will study the functional consequences of defects in the intracellular calcium homeostasis on atrial electrical activity and arrhythmogenesis. Among the specific goals we have are:
- Set-up of a human atrial myocyte model (single cell and 2D model) with detailed SR calcium handling (CSQ buffering, SERCA activíty, RyR2 gating) and calcium activated potassium channels.
- Study the functional consequences of alterations in CSO-mediated calcium buffering, SERCA activity and RyR2 gating.
- Address the cross-talk between calcium handling and SK3-channels in the regulation of atrial electrical activity.
- Modify the atrial myocyte model to investigate how electro-mechanical coupling affects atrial electrical activity.
- Introduce subcellular structure in the atrial model. Study of the conditions for local calcium ralease events, calcium waves and membrane depolarizations.
Overall, the results of this project will provide a better understanding of the mechanisms leading to atrial fibrillation and will help to devise better means to detect and treat it.
Adm. Estat
Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016
Call year
Funcding program
Programa Estatal de I+D+i Orientada a los Retos de la Sociedad
Funding call
Retos de Investigación: Proyectos de I+D+i
Grant institution
Gobierno De España. Ministerio De Economía Y Competitividad, Mineco


Scientific and technological production

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