A5075865473- Cardiac electrophysiology and arrhythmias
- Cardiomyopathy and Myosin Studies
- Ion channel regulation and function
- Pluripotent Stem Cells Research
- Neuroscience and Neural Engineering
- Blood disorders and treatments
- Congenital heart defects research
- Endoplasmic Reticulum Stress and Disease
- CRISPR and Genetic Engineering
- Cardiovascular Effects of Exercise
- Autophagy in Disease and Therapy
- Mitochondrial Function and Pathology
- Heat shock proteins research
- Cardiovascular Function and Risk Factors
- Erythrocyte Function and Pathophysiology
- Viral Infections and Immunology Research
- Cannabis and Cannabinoid Research
- Single-cell and spatial transcriptomics
- Mass Spectrometry Techniques and Applications
- Hyperglycemia and glycemic control in critically ill and hospitalized patients
- Cellular Mechanics and Interactions
- Cardiac Fibrosis and Remodeling
- Cardiac Structural Anomalies and Repair
- Congenital Heart Disease Studies
- Nuclear Structure and Function
University of Delaware
2021-2024
Cardiovascular Institute of the South
2016-2024
Stanford University
2016-2024
Zionsville Community High School
2024
California Institute for Regenerative Medicine
2019
University of Cincinnati Medical Center
2009-2018
Sabin Vaccine Institute
2015
University of Cincinnati
2005-2015
Columbia University
2015
Peking University
2012
Induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) have enormous potential for the study of human cardiac disorders. However, their physiological immaturity severely limits utility as a model system and adoption drug discovery. Here, we describe maturation media designed to provide oxidative substrates adapted metabolic needs iPSC (hiPSC)-CMs. Compared with conventionally cultured hiPSC-CMs, metabolically matured hiPSC-CMs contract greater force show an increased reliance on...
Background: Molecular targeted chemotherapies have been shown to significantly improve the outcomes of patients who cancer, but they often cause cardiovascular side effects that limit their use and impair patients’ quality life. Cardiac dysfunction induced by these therapies, especially trastuzumab, shows a distinct cardiotoxic clinical phenotype in comparison cardiotoxicity conventional chemotherapies. Methods: We used human pluripotent stem cell–derived cardiomyocyte (iPSC-CM) platform...
Muscular dystrophies (MDs) comprise a group of degenerative muscle disorders characterized by progressive wasting and often premature death. The primary defect common to most MDs involves disruption the dystrophin-glycoprotein complex (DGC). This leads sarcolemmal instability Ca(2+) influx, inducing cellular necrosis. Here we have shown that dystrophic phenotype observed in δ-sarcoglycan–null (Sgcd(–/–)) mice dystrophin mutant mdx is dramatically improved skeletal muscle–specific...
Background: The progression toward low-cost and rapid next-generation sequencing has uncovered a multitude of variants uncertain significance (VUS) in both patients asymptomatic “healthy” individuals. A VUS is rare or novel variant for which disease pathogenicity not been conclusively demonstrated excluded, thus cannot be definitively annotated. VUS, therefore, pose critical clinical interpretation risk-assessment challenges, new methods are urgently needed to better characterize their...
Abstract Aims Diastolic dysfunction (DD) is common among hypertrophic cardiomyopathy (HCM) patients, causing major morbidity and mortality. However, its cellular mechanisms are not fully understood, presently there no effective treatment. Patient-specific induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) hold great potential for investigating the underlying DD in HCM as a platform drug discovery. Methods results In present study, beating iPSC-CMs were generated from healthy...
Hypertrophic cardiomyopathy (HCM) is frequently caused by mutations in myosin-binding protein C3 ( MYBPC3) resulting a premature termination codon (PTC). The underlying mechanisms of how PTC MYBPC3 lead to the onset and progression HCM are poorly understood. This study's aim was investigate molecular pathogenesis associated with utilizing human isogenic induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs).Isogenic iPSC lines were generated from patients harboring (p.R943x;...
Depressed sarcoplasmic reticulum (SR) Ca2+ cycling, a universal characteristic of human and experimental heart failure, may be associated with genetic alterations in key Ca2+-handling proteins. In this study, we identified novel PLN mutation (R25C) dilated cardiomyopathy (DCM) investigated its functional significance cardiomyocyte contractility. Exome sequencing C73T substitution the coding region family DCM. The four heterozygous members had implantable cardiac defibrillators, three...
Significance The massive cell death, associated with a heart attack, is mainly due to disruption of mitochondrial membrane integrity upon activation the permeability transition pore. Thus, it important understand how this pore regulated prevent cardiac death. In study, we reported that hematopoietic-substrate-1 protein X-1 (HAX-1) an inhibitor and promotes survival. HAX-1 works through recruitment chaperone called Hsp90 from cyclophilin-D, major component Displacement cyclophilin-D...
Background: Heat shock proteins (Hsp) are known to enhance cell survival under various stress conditions. In the heart, small Hsp20 has emerged as a key mediator of protection against apoptosis, remodeling, and ischemia/reperfusion injury. Moreover, been implicated in modulation cardiac contractility ex vivo. The objective this study was determine vivo role heart mechanisms underlying its regulatory effects calcium (Ca) cycling. Methods Results: overexpression intact animals resulted...
Rationale: Ischemic heart disease is characterized by contractile dysfunction and increased cardiomyocyte death, induced necrosis apoptosis. Increased cell survival after an ischemic insult critical depends on several cellular pathways, which have not been fully elucidated. Objective: To test the hypothesis that anti-apoptotic hematopoietic lineage substrate-1–associated protein X-1 (HAX-1), recently identified as regulator of cardiac Ca cycling, also may ameliorate injury with insult....
The HS-1 associated protein X-1 (HAX-1) is a ubiquitously expressed that protects cardiomyocytes from programmed cell death. Here we identify HAX-1 as regulator of contractility and calcium cycling in the heart. overexpression reduced sarcoplasmic reticulum Ca-ATPase (SERCA2) pump activity isolated vivo, leading to depressed myocyte kinetics mechanics. Conversely, downregulation enhanced contractility. inhibitory effects were abolished upon phosphorylation phospholamban, which plays...
Excessive iron accumulation in the heart causes overload cardiomyopathy (IOC), which initially presents as diastolic dysfunction and arrhythmia but progresses to systolic end-stage failure when left untreated. However, mechanisms of iron-related cardiac injury how accumulates human cardiomyocytes are not well understood. Herein, using induced pluripotent stem cell-derived (iPSC-CMs), we model IOC screen for drugs rescue phenotypes. Human iPSC-CMs under excess exposure recapitulate...
FLNC truncating mutations ( FLNCtv ) are prevalent causes of inherited dilated cardiomyopathy (DCM), with a high risk developing arrhythmogenic cardiomyopathy. We investigated the molecular mechanisms mutant in pathogenesis DCM (a-DCM) using patient-specific induced pluripotent stem cell–derived cardiomyocytes (iPSC-CMs). demonstrated that iPSC-CMs from two patients different displayed arrhythmias and impaired contraction. ablation similar phenotype, suggesting loss-of-function mutations....
HSPB6/Hsp20 (heat shock protein family B [small] member 6) has emerged as a novel cardioprotector against stress-induced injury. We identified human mutant of HSPB6 (HSPB6S10F) exclusively present in dilated cardiomyopathy (DCM) patients. Cardiac expression this mouse hearts resulted remodeling and dysfunction, which progressed to heart failure early death. These detrimental effects were associated with reduced interaction HSPB6S10F BECN1/Beclin 1, leading BECN1 ubiquitination its...
Calcium channel blockers (CCBs) are an important class of drugs in managing cardiovascular diseases. Patients usually rely on these medications for the remainder their lives after diagnosis. Although acute pharmacological actions CCBs hearts well-defined, little is known about drug-specific effects human cardiomyocyte transcriptomes and physiological alterations long-term exposure.This study aimed to simulate chronic CCB treatment examine both functional transcriptomic changes...
Truncating mutations in filamin C (FLNC) are associated with dilated cardiomyopathy and arrhythmogenic cardiomyopathy. FLNC is an actin-binding protein known to interact transmembrane structural proteins; hence, the ablation of cardiomyocytes expected dysregulate cell adhesion, cytoskeletal organization, sarcomere integrity, likely nuclear function. Our previous study showed that transcriptional profiles homozygous deletions human pluripotent stem cell-derived (hiPSC-CMs) highly comparable...