Research projects

This project proposal aims to develop a new therapeutic approach to address arrhythmias and sudden cardiac death in patients with inheritable cardiac diseases like Andersen-Tawil Syndrome type 1 (ATS1) and Duchenne Muscular Dystrophy (DMD). We have identified a macromolecular complex, known as a "channelosome," which contains NaV1.5 the channel responsible for the sodium inward current (INa) and Kir2.1, the strong inward rectifier potassium channel responsible for (IK1). Together these two important membrane channels control ventricular electrical excitability and impulse conduction velocity. Dysfunction of either channel is associated with arrhythmias and sudden cardiac death (SCD). The project focuses on the rational design, characterization, and use of channelosome-rescuing peptides (CRPs) to improve cardiac excitability and prevent SCD. The hypothesis is that advanced targeted therapy based on CRPs containing a critical domain of a1-syntrophin (CRP-SYN) or SAP97(CRP-SAP), both capable of anchoring Kir2.1-NaV1.5 channelosomes at the cell membrane, is a more effective alternative for preventing lifethreatening ventricular arrhythmias than currently available strategies. The project involves a multidisciplinary approach, including the use of mouse and human cell models of both ATS1 and DMD, peptide-based gene therapy via adeno-associated viruses, ECG, intracardiac stimulation, patch-clamp, optical mapping, RNAseq, molecular biology, proteomics, immunohistochemistry, super-resolution (expansion) microscopy, and bioinformatics. If successful, the objectives of the project will provide novel mechanistic understanding and new antiarrhythmic peptides that will advance therapy for life-threatening cardiac diseases.