Elucidating the Role of Biomechanical Strain in Atrial Physiology and Arrhythmias

阐明生物力学应变在心房生理和心律失常中的作用

• 批准号: 10750632
• 负责人: Ilhan Gokhan
• 金额: $ 3.26万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-16 至 2027-09-15
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10750632
• 关键词: Affect; American; Animal Model; Anticoagulation; Arrhythmia; Atrial Fibrillation; Atrial Function; Biological Assay; Biomechanics; Biomedical Engineering; Biophysical Process; Bioreactors; Ca(2+)-Calmodulin Dependent Protein Kinase; Calcium; Cardiac; Cardiac Myocytes; Cardiovascular Diseases; Cardiovascular system; Characteristics; Clinical; Data; Development; Disease; Disease model; Electron Microscopy; Electrophysiology (science); Environment; Esthesia; Evaluation; Fibroblasts; Fibrosis; Foundations; Functional disorder; Future; Gel; Gene Expression; Genes; Genetic Techniques; Goals; Heart Atrium; Heart Diseases; Heart failure; Human; Iatrogenesis; Impairment; In Vitro; Inflammatory; Intervention; Investigation; Ion Channel; Kinetics; Knowledge; Learning; Left; Maps; Measures; Mechanical Stress; Mechanics; Mediating; Methodology; Modeling; Morbidity - disease rate; Motivation; Myofibroblast; Myosin ATPase; Optics; Pathogenesis; Pathologic; Pathology; Pathway interactions; Phase; Phenotype; Physicians; Physiological; Physiology; Population; Predisposition; Protein Analysis; Protein Isoforms; Proteins; Protocols documentation; Pulmonary veins; Quality of life; Regulation; Reproducibility; Resolution; Risk Factors; Role; Scientist; Signal Transduction; Stress; Stroke; Symptoms; System; Techniques; Technology; Testing; Tissues; Training; Universities; Up-Regulation; Work; cardiac tissue engineering; career; clinical imaging; conditioning; design; electrical property; improved; in vitro Model; in vivo; induced pluripotent stem cell; mechanical force; mechanical load; mechanical properties; medical schools; mortality; muscle physiology; novel; novel strategies; pharmacologic; pressure; side effect; standard of care; stem cell biology; symptom treatment; targeted treatment; translational potential

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

项目概要/摘要 动机：心房颤动 (AF) 的负担及其临床后果，包括中风、心脏病 预计未来几十年，失败和生活质量下降将急剧增加。 尽管如此，目前很少有缓解疾病的疗法，而且对症治疗也受到副作用的限制。 该提案利用心脏组织生物力学的基本发现，采用一种新颖的方法 心律失常发病机制，揭示健康心房功能的生物物理机制和 病理性、促心律失常的重塑的动机是准确地模拟心房生理学和 在病理学方面，我们使用人类诱导多能干细胞 (hiPSC) 衍生的工程心脏组织 (EHT) 和 机电生物反应器来区分“健康”与“患病”机械负荷 目标：在目标 1 中， 受生理启发的生物力学应变应用于心房 EHT，以提高其功能成熟度 基因表达、收缩和电生理水平的成功完成将广泛地实现这一目标。 提高工程心脏组织在心房疾病模型中的适用性，目标 2：心房的基质。 对心房 EHT 施加病理性机械应变会诱发心律失常。 机械应变直接受到临床影像学结果的启发，值得注意的是，异常的机械负荷。 组织导致收缩功能障碍，同时上调病理重塑基因，例如 α- SMA 和钙调蛋白激酶这表明常见的机械敏感途径可能是一种有吸引力的途径。 新型 AF 疗法的上游目标 培训：为了进行这些研究，申请人将进行研究。 干细胞生物学、工程心脏组织发育、体外电生理学和电子学的新知识 培训计划由互补领域（生物医学）的两位共同发起人监督。 工程学/肌肉生理学和电生理学），将强调获取新的科学知识 和专业知识；体外疾病模型的严谨性、可重复性和普遍性； 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，并全力支持申请人未来的职业目标。 相关性：房颤影响。 数百万美国人，其中 10% 是 80 岁以上的人。