Summary
This project aims to elucidate the molecular and cellular mechanisms of calcium-induced arrhythmias in arrhythmogenic right ventricular cardiomyopathy (ARVC) using a PKP2-deficient mouse model, with the long-term goal of identifying potential drug targets.
What they want
The project focuses on the microdomain where Ca2+ regulation takes place, hypothesizing that dysfunction of the cardiac ryanodine receptor (RyR2) and ensuing Ca2+ mishandling are critical triggers of cardiac arrhythmia in PKP2cKO mice and ARVC. The work involves three aims: 1) Determine the role of protein kinase C (PKC) phosphorylation in the regulation of RyR2 channel function and calcium homeostasis, specifically at the Thr2810 site. 2) Define the contribution of RyR2 dysfunction, particularly phosphorylation at Thr2810 and Ser2030, in the onset and progression of heart disease in PKP2cKO mice, testing if inhibition prevents arrhythmia and sudden death. 3) Test the efficacy of RyR2 modulators for the prevention of arrhythmia in PKP2-deficient hearts, hypothesizing pharmacological modulation is beneficial.
Deliverables
- Significant insight into the regulation of RyR2 function in a model of PKP2cKO deficiency
- Advancement of RyR2 as a potential therapeutic target to reduce the risk of arrhythmias and increase life-expectancy of patients with ARVC
Technical requirements
- Use of tamoxifen (TAM)-induced ablation of PKP2 (PKP2cKO) mouse model
- Focus on Ca2+ handling and regulation
- Investigation of cardiac ryanodine receptor (RyR2) function
- Analysis of protein kinase C (PKC) phosphorylation of RyR2 at Thr2810 and Ser2030
- Testing of RyR2 modulators
