Board Certification
Cardiovascular Disease, 2012

My research program primarily focuses on hypertrophic cardiomyopathy (HCM), the most common genetic cardiovascular disease of Mendelian inheritance. Our research program integrates basic, translational and clinical science. We have a strong interest in learning how genetic and non-genetic factors (particularly exercise) influence the cardiovascular phenotype and clinical outcomes in patients. We have pursued these questions through a large multicenter registry and several clinical trials. To better understand the molecular pathophysiology of HCM, we leverage a variety of resources and model systems, including human heart tissue from genotyped HCM patients, exogenous expression of sarcomere gene mutations in primary cardiac myocytes, and a series of human inducible pluripotent stem cell-derived cardiac myocyte (hiPSC-CM) models of hypertrophic cardiomyopathy in isogenic lines through genome-editing, as well as patient-derived iPSC lines. Our early work focused on defining gene and allele-specific sarcomere gene expression and specific alterations in calcium homeostasis in human HCM. In recent years, we have primarily focused on myosin binding protein C (MYBPC3), the gene that harbors the largest number of mutations causal for hypertrophic cardiomyopathy. In human myocardium from patients with MYBPC3 mutations, we have defined loss-of-function, or haploinsufficiency of MYBPC3, as the primary pathophysiology. Our lab has identified a critical regulator, the HSP70 family of molecular chaperones, in the turnover of MYBPC3 and are pursuing this pathway as a possible therapeutic target. We have recently completed a small molecule screen of ~2500 compounds in patient-derived iPSC-CMs and have identified a number of other putative candidates that could restore haploinsufficiency of MYBPC3 caused by mutations in this gene.