CAREER: Understanding Atrial Arrhythmia Mechanisms with Patient-derived Engineered Tissues

点击翻译按钮获取中文摘要

Atrial fibrillation (AFib) is the most common electrical conduction disorder in the heart, yet the underlying cause of AFib is poorly understood, particularly when a single gene is not responsible such as in Wolff-Parkinson-White (WPW) syndrome, a disorder in which an extra electrical pathway between the heart's upper and lower chambers causes a rapid heartbeat. The goal of this CAREER project is to develop patient-specific cellular engineered tissue models and computer models to study the roles of arrhythmic triggers, including biomechanical and emotional stress. The electrical and contractile properties of cardiac tissues engineered using stem cells obtained from WPW patients and healthy family members will be measured as the tissues are stretched and/or exposed to physiological stimulants. The knowledge gained from experiments and computer models will facilitate therapeutic development and improve patient care, thus advancing national health. Through supporting outreach and education, the project advances NSF’s mission to increase diversity and inclusion in STEM by addressing a need for cultural change in the Providence community through school science programs and art designed to engage and empower underrepresented students, parents, teachers, and the public. Activities include launching an “Engineering the Heart” 3rd grade module with teacher training and hands-on curricula and developing a science art exhibit for parents and the public to increase engagement in STEM education and encourage cultural change for equity in STEM.The investigators’s research focus is on improving human heart health through developing novel technologies and platforms for regenerating muscle, predicting toxicity, and understanding disease. Consistent with this focus, the goal of this CAREER project is to understand how ion currents and tissue geometry initiate and sustain arrhythmias in WPW like fast heart rate and AFib. As the mechanisms underlying atrial arrhythmia are often multi-factorial, driven by structural and electrophysiological remodeling in atrial tissue, there is a significant need for developing experimental platforms that can isolate arrhythmia mechanisms in order to dissect atrial arrhythmias and enable therapeutic development. To address this need, novel human in vitro and computational models will be developed to enable individual perturbations and their combinations to elicit arrhythmic phenotypes in excitation and contraction. Physiological function will be assessed in 3D engineered tissues containing patient-derived human induced pluripotent stem cell (hiPSC)-derived atrial cardiomyocytes to address the hypothesis that mechanical stretch, a correlate of high blood pressure, and emotional stress (activation of β-adrenergic pathways or the “fight-or-flight” response) will increase automaticity, frequency-dependent contractions, and conduction irregularities to reveal reentry pathways. The research objectives are to (1) derive new patient and control hiPSC lines and evaluate differentiated atrial cardiomyocytes for atrial specificity and WPW phenotype, (2) use 3D engineered tissues to evaluate excitation and contraction responses to atrial-specific ion channel modulators and use our computational action potential model to understand hiPSC-atrial cardiomyocyte ion currents in WPW, and (3) use 3D experimental and computational macrotissues to assess how stretch and β-adrenergic stimulation modulate arrhythmic phenotypes of excitation and contraction. This research project will advance the capabilities in research to study and understand diverse arrhythmia mechanisms with tailored engineered tissue to improve the diagnosis, stratification, health, and quality of life for millions of patients with AFib.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.