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瘤性右心室心肌病（ARVC）发病机制的分子机制的研究。虽然它是一种相对罕见的疾病，但由于以下几个原因，应该对ARVC进行研究：它具有异常引人注目的致突变表型（它是已知的最具致突变性的心脏病）;单基因原因涉及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变异表明存在猝死风险的强大调节剂。未来定义这些修饰物的研究可以为基于机制的治疗确定新的靶点，以防止致命的心律失常（我们非常缺乏的东西）。ARVC的一个主要特征是室性心律失常的发生率非常高，室性心律失常发生在疾病自然史的早期，并且通常先于显著的心室重塑或收缩功能障碍的发展。虽然在确定导致ARVC的桥粒基因突变方面取得了重要进展，但对突变蛋白如何引起疾病的了解要少得多。一个主要的假设是，异常的细胞-细胞粘附损伤心肌细胞并促进细胞死亡和随后的纤维脂肪组织替代。这种机制几乎肯定会发挥作用。然而，桥粒蛋白可能履行双重作用，作为结构蛋白在粘附连接和信号分子，可以抑制Wnt信号，从而调节病理基因表达，促进心肌细胞凋亡，并可能介导表达的纤维化和/或脂肪形成表型。其中一种或两种机制都可能导致缝隙连接重构作为ARVC的早期表现，但实际上对负责机制知之甚少。我们已经发现桥粒蛋白斑珠蛋白（又名3-连环蛋白）从连接池到细胞内池的再分布发生在几乎所有的ARVC病例中，无论涉及的特定突变如何，甚至当没有突变可以被识别时。这有力地表明，斑珠蛋白通过最终的共同途径在疾病发病机制中起着重要作用。因此，拟议的研究特别关注编码斑珠蛋白基因（2057 del 2和S39_K40insS）中两种不同的疾病相关突变以及它们如何导致ARVC。使用最先进的体外方法和新的动物模型，我们将测试ARVC的假设，即通过一个共同的最终途径，其中斑珠蛋白的亚细胞再分布起着关键作用，从受损的细胞生物力学特性和病理扰动Wnt信号。这一统一的假设为临床观察提供了一个新的、可检验的解释，即ARVC患者经常在剧烈运动后发生急性加重。因此，我们将测试这样的假设，即机械应力，例如可能发生在剧烈或长时间运动后，使心脏（特别是右心室）中的桥粒不稳定，这导致斑珠蛋白的细胞质浓度增加，然后导致病理信号应答。 公共卫生相关性：该项目旨在通过定义致心脏病性右心室心肌病（ARVC）的基本机制来促进我们对心脏性猝死（一种主要的公共卫生瘟疫）的理解。虽然ARVC是一种相对罕见的疾病，但它具有任何人类心脏病猝死的最大风险。我们已经对导致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，不仅在ARVC中，而且在更常见的心脏病中。我们的最终目标是帮助开发基于机制的疗法，以防止猝死。

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.