A5034763430- Cardiomyopathy and Myosin Studies
- Cellular Mechanics and Interactions
- Cardiovascular Effects of Exercise
- RNA Research and Splicing
- Tissue Engineering and Regenerative Medicine
- Congenital heart defects research
- Electrospun Nanofibers in Biomedical Applications
- Force Microscopy Techniques and Applications
- Williams Syndrome Research
- Elasticity and Material Modeling
- Cardiac Fibrosis and Remodeling
- Muscle Physiology and Disorders
- Viral Infections and Immunology Research
Boston University
2020-2024
Washington University in St. Louis
2018-2021
Hypertrophic cardiomyopathy (HCM) is caused by pathogenic variants in sarcomere protein genes that evoke hypercontractility, poor relaxation, and increased energy consumption the heart patient risks for arrhythmias failure. Recent studies show missense myosin, molecular motor of sarcomere, are clustered residues participate dynamic conformational states proteins. We hypothesized these conformations essential to adapt contractile output conservation pathophysiology HCM results from...
Significance One of the outstanding challenges in understanding familial dilated cardiomyopathy has been connecting mutation-induced changes sarcomeric protein function with phenotype seen cells. Many contractility at molecular scale are subtle, begging question how they lead to a devastating progressive disease. Here, we show that disease-causing mutations proteins affect not only contraction but also cardiomyocytes sense and respond their mechanical environment associated aging disease...
To assess the genetic architecture of hypertrophic cardiomyopathy (HCM) in patients predominantly Chinese ancestry.We sequenced HCM disease genes Singaporean (n=224) and controls (n=3634), compared findings with additional populations White cohorts (n=6179), performed vitro functional studies.Singaporean had significantly fewer confidently interpreted variants (pathogenic/likely pathogenic: 18%, P<0.0001) but an excess uncertain significance (24%, P<0.0001), as to Whites 31%, significance:...
PKP 2 mutations lead to instability in cell-cell junctions and sarcomeres that impairs cardiac tissue contractility ACM.
Familial hypertrophic cardiomyopathy (HCM), a leading cause of sudden cardiac death, is primarily caused by mutations in sarcomeric proteins. The pathogenesis HCM complex, with functional changes that span scales, from molecules to tissues. This makes it challenging deconvolve the biophysical molecular defect drives disease downstream cellular function. In this study, we examine an mutation troponin T, R92Q, for which several models explaining its effects have been put forward. We...
Hypertrophic cardiomyopathy (HCM) is characterized by thickening of the left ventricular wall, diastolic dysfunction, and fibrosis, associated with mutations in genes encoding sarcomere proteins. While vitro studies have used human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) to study HCM, these models not examined multicellular interactions involved fibrosis. Using engineered cardiac microtissues (CMTs) composed HCM-causing MYH7 -variant hiPSC-CMs wild-type fibroblasts,...
Abstract The structural and functional maturation of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) is essential for pharmaceutical testing, disease modeling, ultimately therapeutic use. Multicellular 3D-tissue platforms have improved the hiPSC-CMs, but probing cardiac contractile properties in a 3D environment remains challenging, especially at depth live tissues. Using small-angle X-ray scattering (SAXS) imaging, we show that hiPSC-CMs matured examined exhibit...
Abstract Familial hypertrophic cardiomyopathy (HCM), a leading cause of sudden cardiac death, is primarily caused by mutations in sarcomeric proteins. The pathogenesis HCM complex, with functional changes that span scales from molecules to tissues. This makes it challenging deconvolve the biophysical molecular defect drives disease downstream cellular function. Here, we examined mutation troponin T, R92Q. We demonstrate primary insult driving mutation-induced alterations tropomyosin...
Abstract Familial dilated cardiomyopathy (DCM) is a leading cause of sudden cardiac death and major indicator for heart transplant. The disease frequently caused by mutations sarcomeric proteins; however, it not well understood how these molecular lead to alterations in cellular organization contractility. To address this critical gap our knowledge, we studied the consequences DCM mutation troponin-T, ΔK210. We determined mechanism ΔK210 used computational modeling predict that should reduce...
Background: Heterozygous truncating variants in the sarcomere protein titin (TTN) are most common genetic cause of heart failure, a major morbidity and mortality. This causality indicates that even two-fold changes amount TTN can profoundly disturb cardiac physiology. Although critical role formation cardiomyocyte contractility is well established, mechanisms regulating transcription gene remain poorly understood. Methods: We performed bioinformatics analysis to identify putative...
Familial cardiomyopathies are the leading cause of sudden cardiac death in young people, affecting more than 1 500 people. Two common forms, hypertrophic (HCM) and dilated (DCM) cardiomyopathies, characterized by remodeling heart tissue, frequently accompanied fibrosis myocyte disarray. These diseases primarily caused mutations sarcomeric proteins that regulate contraction heart; however, it is not clear how these point at molecular level lead to disease phenotype seen patients. To better...
Familial dilated cardiomyopathy (DCM) is a leading cause of sudden cardiac death and major indicator for heart transplant. The disease frequently caused by mutations sarcomeric proteins; however, one the outstanding challenges in field has been connecting mutation-induced changes molecular function with phenotype seen cardiomyocytes. Many DCM contractility at scale are subtle, begging question what other factors could link molecular-scale contractile proteins cellular phenotype. We...