Elucidating the Role of Biomechanical Strain in Atrial Physiology and Arrhythmias

项目总结/摘要 动机：房颤（AF）的负担及其临床后果，包括中风、心脏病、 在未来几十年中，预期失败和生活质量下降将急剧增加。 尽管如此，很少有疾病修饰疗法存在，并且对症治疗受到副作用的限制。 利用心脏组织生物力学的基本发现，该提案采用了一种新颖的方法， 心律失常发病机制，揭示健康心房功能的生物物理机制， 病理性的促血管重塑出于对心房生理学进行准确建模的愿望， 在病理学方面，我们使用人诱导多能干细胞（hiPSC）衍生的工程化心脏组织（EHT）和 机电生物反应器，以描绘“健康”与“患病”的机械负荷。目标：在目标1中， 生理学激发的生物力学应变被应用于心房EHT，以改善其在 基因表达、收缩和电生理水平。这一目标的成功实现将广泛 增加工程心脏组织用于心房疾病建模的适用性。在目标2中，心房肌的基质 心律失常将通过对心房EHT施加病理性机械应变而诱发。这些异常 机械应变直接受到临床成像发现的启发。值得注意的是， 组织引起收缩功能障碍，沿着病理性重塑基因的上调，如α- SMA和钙调蛋白激酶。这表明一个共同的机械敏感途径可能是一个有吸引力的 新型房颤治疗的上游靶点。培训：为了进行这些调查，申请人将继续 在干细胞生物学、工程心脏组织发育、体外电生理学和电子 显微镜培训计划由两个互补领域（生物医学和生物医学）的共同赞助者监督， 工程/肌肉生理学和电生理学），将强调获得新的科学知识 和专业知识;体外疾病模型的严谨性、可重复性和可推广性;临床相关性;以及 专业发展。该提案将利用耶鲁大学的尖端技术和专业知识 和耶鲁大学医学院，并全力支持申请人的未来职业目标。相关性：AF影响 数以百万计的美国人，以及80岁以上的10%。的

PROJECT SUMMARY/ABSTRACT MOTIVATION: The burden of atrial fibrillation (AF) and its clinical consequences, which include stroke, heart failure, and decreased quality of life, are expected to increase dramatically over the next several decades. Despite this, few disease-modifying therapies exist, and symptomatic treatments are limited by side effects. Leveraging fundamental discoveries in cardiac tissue biomechanics, this proposal takes a novel approach to arrhythmia pathogenesis, uncovering biophysical mechanisms that underlie healthy atrial function and pathological, pro-arrhythmic remodeling. Motivated by a desire to accurately model atrial physiology and pathology, we use human induced pluripotent stem cell (hiPSC)-derived engineered heart tissue (EHT) and an electro-mechanical bioreactor to delineate “healthy” vs “diseased” mechanical loading. AIMS: In Aim 1, physiologically-inspired biomechanical strain is applied to atrial EHTs to improve their functional maturity at the gene expression, contractile, and electrophysiological level. Successful completion of this aim will broadly increase the applicability of engineered heart tissue for atrial disease modeling. In Aim 2, a substrate for atrial arrhythmias will be induced by imposing pathological mechanical strain on atrial EHTs. These abnormal mechanical strains are directly inspired by clinical imaging findings. Notably, abnormal mechanical loading of tissue causes contractile dysfunction, along with upregulation of pathological remodeling genes, such as α- SMA and calmodulin kinase. This suggests that a common, mechanosensitive pathway may be an attractive upstream target for novel AF therapies. TRAINING: To enable these investigations, the applicant will pursue new learning in stem cell biology, engineered heart tissue development, in vitro electrophysiology, and electron microscopy. The training plan, overseen by two co-sponsors in complementary fields (biomedical engineering/muscle physiology and electrophysiology), will emphasize acquisition of new scientific knowledge and expertise; rigor, reproducibility, and generalizability of in vitro disease models; clinical correlations; and professional development. The proposal will leverage cutting-edge technology and expertise at Yale University and Yale School of Medicine, and fully support the applicant’s future career goal. RELEVANCE: AF affects millions of Americans, and 10% of those over 80. The