P3: Biophysical Mechanisms in two Arhythmogenic Diseases

P3：两种致心律失常疾病的生物物理机制

• 批准号: 8122106
• 负责人: OMER BERENFELD
• 金额: $ 28.92万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8122106
• 关键词: 3-Dimensional; Adherent Culture; Adipose tissue; Arrhythmia; Arrhythmogenic Right Ventricular Dysplasia; Biological; Calcium; Canis familiaris; Cardiac; Cardiac Myocytes; Cardiomyopathies; Cell Adhesion Molecules; Cell Culture Techniques; Cells; Cessation of life; Characteristics; Clinical; Collaborations; Complex; Computer Simulation; Coupling; Data; Deposition; Disease; Distal; Dysplasia; Extravasation; Fiber; Fibroblasts; Functional disorder; Gap Junctions; Gene Mutation; Generations; Genes; Heart; Histopathology; Homeostasis; Human; Immunohistochemistry; Incidence; Individual; Infiltration; Inherited; Intercalated disc; Ion Channel; Kinetics; Lead; Left; Life; Maintenance; Maps; Mechanics; Modeling; Mus; Muscle; Muscle Cells; Mutate; Mutation; Myocardium; Optics; Pathologic; Pathway interactions; Patients; Pattern; Process; Proteins; Rattus; Regulation; Right ventricular structure; Risk; Role; Ryanodine; Ryanodine Receptor Calcium Release Channel; Ryanodine Receptors; Safety; Sarcoplasmic Reticulum; Secondary to; Side; Simulate; Site; Source; Staging; Structure; Structure of purkinje fibers; System; Tachycardia; Testing; Thick; Tissues; Translating; Ventricular; Ventricular Fibrillation; Ventricular Tachycardia; Work; base; density; design; desmoplakin; genetic regulatory protein; human disease; insight; mathematical model; monolayer; plakophilins; premature; programs; receptor; research study; simulation; sudden cardiac death; three-dimensional modeling; two-dimensional; vector

This project focuses on biophysical principles of arrhythmogenic mechanisms underlying two inherited diseases: arrhythmogenic right ventricular cardiomyopathy (ARVC) and catecholaminergic polymorphic ventricular tachycardia (CPVT). In both cases, arrhythmias and sudden cardiac death (SCO) develop. However, the specific mechanisms underlying ventricular tachycardia/fibrillation (VTA/F) and SCO in either ARVC or CPVT patients has not yet been resolved. In ARVC, arrhythmias may result from impaired mechanical coupling between cardiomyocytes due to mutations in desmosomal proteins, which may lead to dysfunction of the intercalated disk, and eventual disruption of gap junction plaques, myocyte death and fibro-fatty replacement. In CPVT arrhythmias are the result of abnormal calcium regulation due to leaky mutated ryanodine type-2 receptor channels in the sarcoplasmic reticulum. Yet, it is unknown whether the arrhythmias originate in the 3-dimensional myocardium or in the more isolated, cable-like Purkinje network. Our general hypothesis is that regardless of the mechanism(s) by which arrhythmias are triggered in ARVC and CPVT, the final common pathway in the mechanism underlying VTA/F is wavebreak and reentry. The project combines expertise in cell culture, optical mapping, histopathology, immunohistochemistry and computer modeling to provide testable predictions about how alterations of either structural or Ca2+ regulatory proteins translate into electrical abnormalities that ultimately result in VTA/F and SCO. We propose four Specific Aims: 1) To determine electrophysiological consequences of fibroblast replacement of myocytes and of alterations in intercellular coupling in ventricular constructs and their role in the genesis of reentry in ARVC. 2) To establish the individual roles of alterations in intercellular coupling and fibro-fatty deposits in the genesis of arrhythmias in 3D models of the dysplasic right ventricle. 3) To investigate mechanisms of triggering and maintenance of reentry in biological and numerical models using 2D patterns of CPVT-like mutated mouse cells, mimicking the Purkinje network and the Purkinje-muscle junction. 4) To investigate mechanisms of VT initiation and the transition to VF in simulations using a realistic 3D model of the CPVT-like mutated mouse heart. The proposed work should provide new insight into arrhythmia mechanisms in diseases leading to alterations in the structural and functional homeostasis of the heart.

该项目重点研究两种遗传性致心律失常机制的生物物理学原理 疾病：致心律失常性右心室心肌病（ARVC）和儿茶酚胺能多态性 室性心动过速（CPVT）。在这两种情况下，都会出现心律失常和心源性猝死（SCO）。 然而，室性心动过速/颤动 (VTA/F) 和 SCO 的具体机制 ARVC或CPVT患者的问题尚未得到解决。在 ARVC 中，心律失常可能是由受损引起的 由于桥粒蛋白突变导致心肌细胞之间的机械耦合，这可能导致 闰盘功能障碍，最终导致间隙连接斑块破坏、心肌细胞死亡和 纤维脂肪替代品。在 CPVT 中，心律失常是由于渗漏导致钙调节异常的结果。 肌浆网中突变的兰尼碱2型受体通道。然而，尚不清楚是否 心律失常起源于三维心肌或更孤立的、电缆状的浦肯野网络。 我们的一般假设是，无论 ARVC 中触发心律失常的机制如何 和 CPVT，VTA/F 机制的最终共同途径是波破和折返。这 该项目结合了细胞培养、光学绘图、组织病理学、免疫组织化学和 计算机建模提供关于结构或 Ca2+ 如何改变的可测试预测 调节蛋白转化为电异常，最终导致 VTA/F 和 SCO。我们 提出四个具体目标：1）确定成纤维细胞替代的电生理后果 心肌细胞和心室结构中细胞间耦合的改变及其在发生中的作用 重返ARVC。 2) 确定细胞间偶联和纤维脂肪改变的个体作用 发育不良右心室 3D 模型中心律失常发生过程中的沉积物。 3）调查 使用二维模式在生物和数值模型中触发和维持再入的机制 CPVT 样突变小鼠细胞，模仿浦肯野网络和浦肯野肌肉连接。 4) 至 使用真实的 3D 模型在模拟中研究 VT 启动和向 VF 过渡的机制 CPVT 样突变小鼠心脏。拟议的工作应该为心律失常提供新的见解 导致心脏结构和功能稳态改变的疾病机制。