Disease Mechanisms in ARVC

描述(由申请人提供)：这是一项新的申请，旨在资助旨在阐明致心律失常性右室心肌病(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，但有几个原因值得研究：它具有异常戏剧性的致心律失常表型(它是已知的最具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；它高度可变的遗传外显率表明存在强大的猝死风险修饰物。未来定义这些修饰物的研究可能会为基于机制的治疗确定新的靶点，以防止致命的心律失常(这是我们严重缺乏的)。ARVC的一个基本特征是室性心律失常的发生率非常高，这种心律失常发生在疾病自然病程的早期，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，但人们对突变蛋白如何导致疾病知之甚少。一种主要的假说是，异常的细胞-细胞黏附损伤心肌细胞，促进细胞死亡和随后被纤维脂肪组织取代。这样的机制几乎肯定会发挥作用。然而，桥粒蛋白可能作为粘连连接的结构蛋白和信号分子发挥双重作用，可以抑制Wnt信号转导，从而调节病理基因的表达，促进心肌细胞凋亡，并可能介导成纤维和/或成脂表型的表达。作为ARVC的早期表现，两种机制中的一种或两种都可能导致缝隙连接重构，但实际上对其责任机制知之甚少(S)。我们发现，几乎所有的ARVC病例都会发生桥粒蛋白(又名3-连环蛋白)从连接池到细胞内池的重新分布，无论涉及的是什么特定突变，甚至在没有发现突变的情况下也是如此。这强烈地表明，通过最终的共同途径，蛋白在疾病的发病机制中起着基本的作用。因此，拟议的研究主要集中在两种不同的与疾病相关的白蛋白编码基因突变(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，我们将检验这一假说，即ARVC是由细胞生物力学特性受损和Wnt信号的病理扰动通过共同的最终途径产生的，其中蛋白的亚细胞再分布起着关键作用。这一统一的假设为ARVC患者在剧烈运动后经常经历急性加重的临床观察提供了一个新颖的、可检验的解释。因此，我们将检验这一假设，即机械应激，如在剧烈或长时间运动后可能发生的，破坏心脏(特别是右心室)中桥粒的稳定，从而导致细胞质中蛋白球蛋白浓度的增加，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导致心律失常的右室心肌病(ARVC)的基本机制，促进我们对心脏性猝死这一重大公共卫生瘟疫的理解。虽然ARVC是一种相对不常见的疾病，但它是所有人类心脏病中猝死风险最大的。我们对导致ARVC猝死的潜在分子通路有了重大发现。通过本申请中提出的研究，我们希望对猝死有更好的了解，不仅是在ARVC，而且在更常见的心脏病形式中也是如此。我们的最终目标是帮助开发基于机制的疗法来防止猝死。

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.