Emerging evidence suggests an important role for cardiac TRP channels in both atrial and ventricular proarrhythmic remodeling. This project employs mechanistic computational models of cardiomyocytes and fibroblasts to better characterize the role of TRP channels in cardiac calcium-dependent signaling pathways and proarrhythmic remodeling, and to identify potential novel therapeutic targets.
Project Details
Background:
Cardiac remodelling following a pathologic insult to the heart, plays a central role in cardiovascular disease, with subsequent development of cardiac arrhythmias as a major mediator of morbidity and mortality. Emerging evidence suggests an important role for transient receptor potential (TRP) channels, in particular the TRPC subfamily, in both atrial and ventricular proarrhythmic remodeling. However, a quantitative understanding of the downstream signaling pathways and their relative contribution to arrhythmogenesis is lacking.
Hypothesis and Objectives:
Mechanistic computational models of cardiac electrophysiology help to integrate experimental data and enable the identification of nodal points that may constitute promising therapeutic targets. However, none of the currently available models integrate TRPC channels and their downstream effects on Ca2+ handling.1 We aim to develop novel state-of-the-art computational tools (freely available in open-source format) to simulate the effects of TRPC-channel remodeling and their modulation by photo-pharmacological tools, and to use these models to identify novel therapeutic targets.
Methodology:
The PhD student will be trained in computational modeling of cardiac cellular electrophysiology and will develop Markov-model formulations of TRPC channel gating with/without different pharmacological modulators based on existing and newly collected experimental data. The TRPC ion-channel models will be integrated into detailed models of the human atrial and ventricular cardiomyocyte recently developed by the PI (Figure).2 Models will be calibrated based on cardiomyocyte contractility and Ca2+-cycling data obtained by live-cell imaging as part of the TRPC.at project (Holzer) and used to assess the contribution of TRPC to cellular arrhythmogenesis at baseline and in the presence of disease-related TRPC remodeling. The same approach will be used to develop a novel model of the human cardiac fibroblast, integrating key fibroblast ion channels and Ca2+-handling properties based on published data from long-term collaborators of the PI.3 Alterations in fibroblast Ca2+-handling will be considered a key indicator of the pro- or anti-fibrotic consequences of TRPC-channel modulation. Sensitivity analyses employing large populations of virtual fibroblasts and cardiomyocytes with variations in model parameters will identify the parameters associated with proarrhythmic phenotypes with or without TRPC remodeling. Together, these analyses will provide novel quantitative insights into the role of TRPC in proarrhythmic cardiac remodeling.
People Involved
Primary supervisor: Jordi Heijman
Collaborators: Senka Holzer, Oleksandra Tiapko