Year 2
Most heart conditions leading to sudden death or impaired cardiac pumping functions in the young people (<35 years old) are the results of genetic mutations inherited from parents. It is very difficult to find curative therapy for these inherited heart diseases due to late diagnosis and lack of understanding in how genetic mutations cause these diseases. One of these inherited heart diseases is named arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C). The signature features of sick ARVD/C hearts are progressive heart muscle loss and their replacement by fat and scare tissues, which can lead to lethal heart rhythms or heart failure. We made significant breakthrough and successfully modeled sick ARVD/C heart muscles in cell cultures using versatile stem cells derived from ARVD/C patients’ skin cells with genetic mutations in desmosomal (a specific type of cell-cell junctions in hearts) proteins, e.g. plakophilin-2 (Pkp2). These disease-specific stem cells can give rise to heart cells, which allow us to discover specific abnormalities in energy consumption of ARVD/C heart muscles that lead to their dysfunction and death. In Year 2, we continued to create and characterize additional stem cells lines from ARVD/C patients with different desmosomal mutations. As we had published previously, we have confirmed that the same metabolic deregulation occurs in heart muscles derived from new ARVD/C patient-specific stem cells with different mutations from Pkp2. We further explored new microRNA-based pathogenic mechanisms and identified new classes of therapeutic agents to suppress ARVD/C pathologies in culture. We also started to establish a known ARVD/C mouse model for future preclinical drug testing.