FKBP5 AND CARDIAC ARRHYTHMOGENESIS

Baylor College Of Medicine, Houston TX

Investigators

Linked publications & trials

Abstract

PROJECT SUMMARY Atrial fibrillation (AF) is the most frequent arrhythmia. Reduced mRNA expression of FK506-binding protein 5 (FKBP5) was recently discovered in a transcriptomic study with AF patient tissues. However, the functions of FKBP5 in heart are unknown. Preliminary studies revealed that cardiac specific loss of FKBP5 promotes the AF development. The long-term goal of this project is to elucidate the function of FKBP5 in the heart and the underlying arrhythmogenic mechanisms associated with the FKBP5 deficiency, with a view toward developing new therapeutic strategies to reduce AF risk. We will test the overarching hypothesis that the FKBP5 deficiency can enhance atrial arrhythmogenesis via a ‘double-hit’ mechanism, i.e. enhancement of Na+/Ca2+ exchanger 1 - mediated triggered activity in cardiomyocytes, and promotion of fibrotic remodeling due to altered fibroblast function. We will elucidate the proarrhythmic mechanisms due to cardiomyocyte-specific or fibroblast-specific loss of FKBP5, respectively. We will also evaluate the anti-AF potential of targeting the FKBP5 pathway. The proposed studies will unveil the critical role of FKBP5 in regulating cardiac electrophysiology and provide new insights to molecular mechanisms of AF.