Disease Mechanisms in ARVC

描述（由申请人提供）：这是一项新的申请，旨在资助旨在阐明心律失常性右室心肌病（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，ARVC应该被研究：它具有异常戏剧性的致心律失常表型（它是已知的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；它的高度可变的基因外显率表明了猝死风险的强大修饰因子的存在。未来对这些修饰剂的研究可以确定基于机制的治疗方法的新靶点，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，发生在疾病的自然史早期，通常先于显著的心室重构或收缩功能障碍的发展。虽然在鉴定导致ARVC的桥粒体基因突变方面取得了重要进展，但对突变蛋白如何导致该病的了解却少得多。一个主要的假设是异常的细胞-细胞粘附损伤心肌细胞，促进细胞死亡并随后被纤维脂肪组织取代。这种机制几乎肯定起了作用。然而，桥粒体蛋白可能具有双重作用，既是粘附连接中的结构蛋白，也是抑制Wnt信号传导的信号分子，从而调节病理基因表达，促进心肌细胞凋亡，并可能介导纤维性和/或脂肪性表型的表达。其中一种或两种机制都可能导致间隙连接重构作为ARVC的早期表现，但实际上对其机制知之甚少。我们发现，在几乎所有的ARVC病例中，桥粒蛋白血小板红蛋白（又名3-连环蛋白）都发生从连接池到细胞内池的再分配，而不管涉及的具体突变是什么，甚至当没有突变可以确定时。这有力地表明，通过最后的共同途径，血小板红蛋白在疾病发病机制中起着基本作用。因此，拟议的研究特别侧重于编码血小板红蛋白的基因（2057del2和s39_k40ins）中的两种不同的疾病相关突变，以及它们如何引起ARVC。利用最先进的体外方法和新的动物模型，我们将验证ARVC是由细胞生物力学特性受损和Wnt信号的病理扰动共同导致的假设，而在这一共同的最终途径中，血小板红蛋白的亚细胞重新分布起着关键作用。这一统一的假设为临床观察提供了一种新颖的、可检验的解释，即ARVC患者经常在剧烈运动后出现急性加重。因此，我们将验证这样的假设，即机械应力，如剧烈或长时间运动后可能发生的机械应力，使心脏（特别是右心室）的桥粒不稳定，从而导致血小板红蛋白细胞质浓度增加，然后引起病理信号反应。

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.