Disease Mechanisms in ARVC

ARVC 的疾病机制

• 批准号: 8055288
• 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/8055288
• 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）：这是一项新申请，旨在资助旨在阐明致心律失常性右心室心肌病（ARVC）发病机制的分子机制的研究。尽管 ARVC 是一种相对罕见的疾病，但仍应对其进行研究，原因如下：它具有异常显着的致心律失常表型（它是已知最致心律失常的心脏病）；单基因原因暗示了可能适用于更常见形式的心脏病的重要疾病机制；它的高度可变的遗传外显率表明存在对猝死风险的强大修饰因素。未来定义这些修饰因素的研究可以确定基于机制的治疗的新目标，以预防致命性心律失常（这是我们非常缺乏的）。 ARVC 的一个主要特征是室性心律失常的发生率非常高，其发生在疾病自然史的早期，并且通常先于显着的心室重构或收缩功能障碍的发展。虽然在识别导致 ARVC 的桥粒基因突变方面取得了重要进展，但对于突变蛋白如何导致该疾病的了解却少之又少。一种主要的假设是，异常的细胞间粘附会损伤心肌细胞并促进细胞死亡并随后被纤维脂肪组织替代。这样的机制几乎肯定会发挥作用。然而，桥粒蛋白可以发挥双重作用，作为粘附连接中的结构蛋白和作为信号分子，其可以抑制Wnt信号传导，从而调节病理基因表达，促进心肌细胞凋亡，并可能介导纤维形成和/或脂肪形成表型的表达。任何一种或两种机制都可能导致间隙连接重塑作为 ARVC 的早期表现，但实际上人们对其中的机制知之甚少。我们发现，几乎所有 ARVC 病例中都会发生桥粒蛋白板球蛋白（又名 3-连环蛋白）从连接池重新分布到细胞内池的情况，无论涉及何种特定突变，甚至无法识别突变。这强烈表明斑珠蛋白通过最终共同途径在疾病发病机制中发挥着重要作用。因此，拟议的研究重点关注斑球蛋白编码基因中两种不同的疾病相关突变（2057del2 和 S39_K40insS）以及它们如何导致 ARVC。使用最先进的体外方法和新的动物模型，我们将测试以下假设：ARVC 是由受损的细胞生物力学特性和 Wnt 信号传导的病理扰动引起的，通过共同的最终途径，其中斑珠蛋白的亚细胞重新分布发挥作用具有举足轻重的作用。这一统一的假设为 ARVC 患者在剧烈运动后经常出现急性加重的临床观察提供了一种新颖的、可测试的解释。因此，我们将检验这样的假设：机械应力（例如剧烈或长时间运动后可能发生的机械应力）会破坏心脏（尤其是右心室）桥粒的稳定性，从而导致斑珠蛋白的细胞质浓度增加，然后导致病理信号反应。 公共卫生相关性：该项目旨在通过定义致心律失常性右心室心肌病 (ARVC) 的基本机制，增进我们对心源性猝死这一重大公共卫生瘟疫的理解。尽管 ARVC 是一种相对罕见的疾病，但它是所有人类心脏病中猝死风险最大的。我们对导致 ARVC 猝死的潜在分子途径有了重大发现。通过本申请中提出的研究，我们希望能够更好地了解猝死，不仅是 ARVC，而且还有更常见的心脏病形式。我们的最终目标是帮助开发基于机制的疗法来预防猝死。