Disease Mechanisms in ARVC

ARVC 的疾病机制

• 批准号: 8236879
• 负责人: JEFFREY E SAFFITZ
• 金额: $ 42.92万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8236879
• 关键词: Abnormal Cell; Acute; Adhesions; Adipose tissue; Animal Model; Apoptosis; Arrhythmia; Arrhythmogenic Right Ventricular Dysplasia; Attention; Binding; Biology; Biomechanics; Boston; Cardiac; Cardiac Myocytes; Cell Death; Cell-Cell Adhesion; Cells; Cicatrix; Clinical; Commit; Complex; Decision Making; Desmosomes; Detection; Development; Diagnostic tests; Disease; Disease Progression; Exercise; Functional disorder; Funding; Future; Gap Junctions; Gene Expression; Gene Mutation; Genes; Genetic; Goals; Grant; Heart; Heart Diseases; Human; In Vitro; Incidence; Individual; Injury; Intercalated disc; Journals; Laboratories; Lead; Link; Mechanical Stress; Mechanics; Mediating; Molecular; Mutation; Myocardial Degeneration; National Heart, Lung, and Blood Institute; Organ; Paper; Pathogenesis; Pathway interactions; Patients; Penetrance; Phenotype; Plague; Play; Property; Proteins; Public Health; Publishing; Rare Diseases; Research; Research Design; Review Committee; Right ventricular structure; Risk; Role; Running; Signal Pathway; Signal Transduction; Signaling Molecule; Skin Tissue; Solid; Structural Protein; Sudden Death; Testing; Time; Tissues; Transgenic Mice; United States National Institutes of Health; Ursidae Family; Ventricular Arrhythmia; Ventricular Remodeling; Work; Writing; base; clinical phenotype; design; disease natural history; experience; heart rhythm; human disease; improved; injured; insight; interest; medical schools; mouse model; mutant; novel; novel diagnostics; novel strategies; plakoglobin; prevent; programs; public health relevance; response; sudden cardiac death

DESCRIPTION (provided by applicant): This is a new application to fund research designed to elucidate molecular mechanisms in the pathogenesis of arrhythmogenic right ventricular cardiomyopathy (ARVC). Although it is a relatively rare disease, ARVC should be studied for several reasons: it has an unusually dramatic arrhythmogenic phenotype (it is the most arrhythmogenic heart disease known); the monogenic causes implicate important disease mechanisms that are likely to apply to more common forms of heart disease; and it's highly variable genetic penetrance indicates the presence of powerful modifiers of the risk of sudden death. Future studies to define these modifiers could identify new targets for mechanism-based therapies to prevent lethal arrhythmias (something we sorely lack). A cardinal feature of ARVC is a very high incidence of ventricular arrhythmias which occur early in the natural history of the disease and often precede the development of significant ventricular remodeling or contractile dysfunction. While there has been important progress in identifying mutations in desmosomal genes that lead to ARVC, much less is known about how the mutant proteins cause the disease. One leading hypothesis is that abnormal cell-cell adhesion injures cardiac myocytes and promotes cell death and subsequent replacement by fibro-fatty tissue. Such a mechanism almost certainly plays a role. However, desmosomal proteins may fulfill dual roles as structural proteins in adhesion junctions and as signaling molecules which can inhibit Wnt signaling and, thereby, modulate pathological gene expression, promote cardiac myocyte apoptosis and perhaps mediate expression of a fibrogenic and/or adipogenic phenotype. Either or both mechanisms could lead to gap junction remodeling as an early manifestation in ARVC, but little is actually known about the responsible mechanism(s). We have discovered that redistribution of the desmosomal protein plakoglobin (aka 3-catenin) from junctional to intracellular pools occurs in virtually all cases of ARVC regardless of the specific mutation involved or even when no mutation can be identified. This strongly suggests that plakoglobin plays a fundamental role, via a final common pathway, in disease pathogenesis. Accordingly, the proposed research is focused specifically on two different disease-related mutations in the gene encoding plakoglobin (2057del2 and S39_K40insS) and how they cause ARVC. Using state-of-the-art in vitro approaches and new animal models, we will test the hypothesis that ARVC results from both compromised cell biomechanical properties and pathological perturbations in Wnt signaling via a common final pathway in which subcellular re-distribution of plakoglobin plays a pivotal role. This unifying hypothesis provides a novel, testable explanation for the clinical observation that ARVC patients often experience acute exacerbations following intense exercise. Thus, we will test the hypothesis that mechanical stress, such as might occur following strenuous or prolonged exercise, destabilizes desmosomes in the heart (especially in the right ventricle) which leads to increased cytoplasmic concentrations of plakoglobin and, then, to pathological signaling responses. PUBLIC HEALTH RELEVANCE: This project is designed to advance our understanding of sudden cardiac death, a major public health plague, by defining fundamental mechanisms responsible for arrhythmogenic right ventricular cardiomyopathy (ARVC). Although ARVC is a relatively uncommon disease, it carries the greatest risk of sudden death of any human heart disease. We have made a major discovery about the underlying molecular pathway responsible for sudden death in ARVC. Through studies proposed in this application, we expect to gain a greater understanding of sudden death, not only in ARVC but in more common forms of heart disease as well. Our ultimate goal is to help develop mechanism-based therapies to prevent sudden death.

描述（由申请人提供）：这是一种新的应用程序，用于资助旨在阐明心律失常右心室心肌病（ARVC）发病机理的分子机制的研究。尽管它是一种相对罕见的疾病，但应以几种原因对ARVC进行研究：它具有异常的心律失常表型（已知的心律失常心脏病）；单基因原因暗示了可能适用于更常见的心脏病形式的重要疾病机制。这是高度可变的遗传外观，表明存在猝死风险的强大修饰符。定义这些修饰符的未来研究可能会确定基于机制的疗法的新靶标，以防止致命的心律不齐（我们非常缺乏这一点）。 ARVC的基本特征是疾病自然病史早期发生的心室心律不齐的很高的发病率，通常是在明显的心室重塑或收缩功能障碍之前发生之前。尽管在识别导致ARVC的脱骨基因突变方面取得了重要的进展，但对突变蛋白如何引起该疾病的了解却少得多。一个主要的假设是，异常的细胞 - 细胞粘附会损害心肌细胞，并促进细胞死亡，并随后被纤维脂肪组织替代。这种机制几乎肯定起着作用。然而，脱氨理解蛋白可以在粘附连接处和信号分子中作为结构蛋白作为结构蛋白的双重作用，从而可以抑制Wnt信号传导，从而调节病理基因的表达，促进心肌细胞凋亡，并促进纤维源性和/或脂肪生成型的表达。一种或两种机制都可能导致差距重塑作为ARVC中的早期表现，但实际上对负责机理几乎不了解。我们已经发现，在几乎所有涉及的特定突变，即使无法鉴定出任何突变，都会发生脱骨蛋白plakoglobin（aka 3-catenin）的脱骨蛋白plakoglobin（aka 3-catenin）的重新分布。这强烈表明，plakoglobin在疾病发病机理中通过最终的共同途径起着基本作用。因此，拟议的研究专门针对编码plakoglobin（2057del2和s39_k40ins）的两个不同疾病相关的突变，以及它们如何引起ARVC。使用最新的体外方法和新动物模型，我们将测试以下假设：ARVC是由损害Wnt信号传导中受损的细胞生物力学特性和病理扰动引起的，在该途径中，Plakoglobin的亚细胞重新分布在plakoglobin扮演的角色扮演着重要的作用。这个统一的假设为临床观察结果提供了一种新颖的可检验的解释，即ARVC患者在激烈的运动后经常遭受急性加重。因此，我们将检验以下假设：机械应力（例如在剧烈运动或延长运动后可能发生）会破坏心脏中的脱骨体（尤其是在右心室），从而导致plakoglobin的细胞质浓度升高，然后导致对病理信号传导反应的细胞质浓度。 公共卫生相关性：该项目旨在通过定义负责心律失常右心心肌病（ARVC）的基本机制，旨在提高我们对心脏突然死亡的理解，这是一个主要的公共卫生瘟疫。尽管ARVC是一种相对罕见的疾病，但它具有任何人类心脏病突然死亡的最大风险。我们已经对导致ARVC突然死亡的基本分子途径进行了重大发现。通过在本应用中提出的研究，我们希望不仅在ARVC中，而且在更常见的心脏病形式中，对猝死有了更深入的了解。我们的最终目标是帮助开发基于机制的疗法以防止猝死。