Research Projects

Dilated cardiomyopathy (DCM) is a major cause of heart failure and sudden cardiac death, representing a significant global health burden. DCM is characterized by dilation and impaired contraction of left ventricle, leading to progressive heart failure, arrhythmias, and increased mortality. While secondary causes such as ischemic heart disease, toxins, and metabolic disorders contribute to DCM, a substantial proportion of cases are now recognized to have a genetic basis. Recent advances in high-throughput sequencing have revealed that up to 40% of idiopathic DCM cases are attributable to pathogenic variants in genes encoding sarcomeric and cytoskeletal proteins. However, the genetic landscape of DCM is highly heterogeneous, and the functional consequences of many identified variants, particularly splice variants and variants of unknown significance (VUS), remain poorly understood. Among the genes implicated in DCM, ACTN2 (alpha-actinin-2) and FLNC (filamin-C) have emerged as critical components of the cardiac sarcomere and cytoskeleton. ACTN2 is a key Z-disc protein that crosslinks actin filaments, anchors titin, and maintains sarcomere integrity, while FLNC is an actin-binding protein involved in linking the cytoskeleton to the extracellular matrix and facilitating mechanotransduction. Pathogenic variants in ACTN2 and FLNC have been associated with a spectrum of cardiomyopathies, including DCM, hypertrophic cardiomyopathy (HCM), and arrhythmogenic cardiomyopathy (ACM). Despite these associations, the precise molecular and cellular mechanisms by which ACTN2 and FLNC variants lead to DCM are not fully elucidated. This project aims to bridge the gap between genetic discovery and mechanistic understanding by functionally characterizing ACTN2 and FLNC variants using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and advanced molecular profiling techniques. The central hypothesis is that pathogenic variants in ACTN2 and FLNC disrupt sarcomere assembly, impair contractile function, and activate maladaptive cellular stress responses, thereby driving the development and progression of DCM through both shared and gene-specific pathways. The specific objectives of the project are as follows: 1. Investigate the pathogenic mechanisms underlying ACTN2-associated dilated cardiomyopathy. 2. Explore the pathogenic mechanisms driving FLNC-related dilated cardiomyopathy. 3. Identify the interacting partners of ACTN2 and FLNC in cardiomyocytes differentiated from induced pluripotent stem cells (iPSCs). 4. Compare the signaling pathways involved in dilated cardiomyopathy in human embryonic stem cell-derived cardiomyocyte (hESC-CM) models with sarcomere gene mutations. The successful completion of this project will generate new insights into the molecular pathogenesis of DCM, facilitate genotype–phenotype correlations, and identify novel biomarkers and therapeutic targets. By integrating genetic, cellular, and molecular data, the study will advance precision medicine approaches for the diagnosis, risk stratification, and management of patients with inherited cardiomyopathies. Furthermore, the establishment of hiPSC-CM models and functional genomics pipelines will provide valuable resources for the broader cardiovascular research community and lay the groundwork for future translational studies.