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: 7928101
• 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/7928101
• 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; Heart Diseases; 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.

本项目主要探讨两种遗传的心律失常发生机制的生物物理原理