Determinants of Disease Expression in Arrhythmogenic Cardiomyopathy

描述(由申请人提供)： 本申请涉及广泛的挑战领域(15)转化研究和具体挑战主题15-OD(ORDR)-101：预防、早期发现和治疗罕见疾病的试点项目。这项挑战奖励申请的重点是致心律失常性右室心肌病(ARVC)，这是一种罕见的原发心肌疾病，以严重的室性快速性心律失常和心脏性猝死的高发生率为特征，通常发生在收缩功能障碍和心脏重塑1，2的发展之前。它是人类心脏病中最具致心律失常的形式。ARVC患者发生适当ICD电击的频率远高于其他心肌病和离子通道病。因此，了解ARVC发生心律失常的潜在决定因素可能会为更常见形式的心脏病猝死的机制提供新的见解。ARVC是一种家族性疾病。在至少40%的患者中可以发现一个或多个编码桥粒蛋白的基因(桥粒蛋白、桥粒粘连蛋白、桥粒蛋白、蛋白球蛋白、嗜血小板蛋白)发生突变1，2。迄今尚未发现的与桥粒蛋白的结构和信号作用相关的其他编码蛋白的基因突变可能是其余病例中的大部分原因。与其他家族性非缺血性心肌病相比，ARVC的特点是遗传外显率和疾病表现的差异性要大得多。同一家庭中携带相同致病突变的个体具有明显不同的疾病表现并不少见。一个指示病例可能会在年轻时经历心脏性猝死，而具有相同突变的一级亲属可能看起来完全正常，并活到老年。这表明，强大的修饰物可以决定疾病的表现和猝死的风险。然而，人们对这些修饰语几乎一无所知。此外，ARVC唯一有效的治疗方法是植入式心脏除颤器，这种除颤器虽然有可能挽救生命，但价格昂贵，可能会对发病率和生活质量产生重大影响。识别ARVC中疾病表达的决定因素可以提供新的基于机制的治疗1，2。在这项挑战拨款申请中，我们建议使用斑马鱼作为模型系统来发现ARVC中心律失常发生和疾病表达的决定因素。尽管鱼有两室心脏，但鱼和人的心肌细胞和心肌组织具有相同的基本生物学原理、发育途径、基因表达谱以及细胞结构和功能特性3。几乎所有用于治疗心脏病的主要药物在斑马鱼的心脏上都有同源受体、信号级联和生理效应。斑马鱼系统的最大优势是可以快速筛选大量胚胎，以确定心脏结构和功能的变化。成熟、高效的诱变和遗传筛选或小分子筛选方法可应用于鱼胚胎，以无偏见、全基因组的方法识别与特定表型3-5相关的新基因和/或途径。这项提议将两名富有成效的调查人员聚集在一起，他们拥有共同的利益，并致力于创造一种能够取得非凡进展的合作。这是一个新项目。它需要全新的、潜在的非常强大的、非常可行的新研究。如果获得资金，它将创造新的就业机会，并包括购买新的美国制造的设备。实现该项目目标的基本要素已经到位，这项工作很可能会催生一个重大的新研究计划。最后，我们认为，这项工作体现了罕见疾病研究的理想和目标。这不仅有可能对一种罕见但致命的心脏病患者产生直接的积极影响，而且拟议中的研究还可能对美国这个长期缺乏合理治疗目标和策略的领域的主要死亡原因发现新的见解。 公共卫生相关性：该项目旨在促进我们对心脏性猝死这一重大公共卫生瘟疫的理解。我们将研究一种罕见的心脏病，它具有已知的最大猝死风险，并使用一种新的模型系统来识别决定猝死风险的遗传和其他因素。这不仅将帮助患有这种罕见疾病的家庭，也将帮助那些因常见心脏病而面临猝死风险的人。

DESCRIPTION (provided by applicant): This application addresses broad Challenge Area (15) Translational Research and specific Challenge Topic 15-OD(ORDR)-101: Pilot projects for prevention, early detection and treatment of rare diseases. This Challenge Grant application is focused on arrhythmogenic right ventricular cardiomyopathy (ARVC), a rare primary heart muscle disorder characterized by a high incidence of serious ventricular tachyarrhythmias and sudden cardiac death, typically preceding the development of contractile dysfunction and cardiac remodeling1, 2. It is the most arrhythmogenic form of human heart disease. The rate of appropriate ICD shocks in patients with ARVC greatly exceeds that for other cardiomyopathies and the ion channelopathies. Understanding the underlying determinants of arrhythmogenesis in ARVC may, therefore, provide new insights into mechanisms of sudden death in more common forms of heart disease. ARVC is a familial disease. Mutations in one or more genes encoding desmosomal proteins (desmoglein, desmocollin, desmoplakin, plakoglobin, plakophilin) can be identified in at least 40% of affected individuals1, 2. As yet undiscovered mutations in other genes encoding proteins related to the structural and signaling roles of desmosomal proteins presumably account for many if not all of the remaining cases. Compared to other familial non-ischemic cardiomyopathies, ARVC is characterized by far greater variability in genetic penetrance and disease manifestation1. It is not unusual for individuals within the same family who harbor the same disease- causing mutation to have dramatically different manifestations of disease. An index case may experience sudden cardiac death at a young age whereas a first degree relative with the same mutation may appear entirely normal and survive to old age. This indicates that powerful modifiers act to determine disease expression and risk of sudden death. However, virtually nothing is known about these modifiers. Furthermore, the only effective treatment for ARVC is an implantable cardiac defibrillator which although potentially lifesaving, is expensive and can be associated with significant impact on morbidity and quality-of-life. Identification of determinants of disease expression in ARVC could provide new mechanism-based therapies1, 2. In this Challenge Grant Application, we propose to use zebrafish as a model system to discover determinants of arrhythmogenesis and disease expression in ARVC. Although fish have 2-chambered hearts, the same fundamental biological principals, developmental pathways, genetic expression profiles, and cellular structure and function properties apply to the cardiac myocytes and myocardial tissues of fish and humans3. Virtually all of the major drugs used to treat heart disease in patients have homologous receptors, signaling cascades and physiological effects in the zebrafish heart. The great advantage of the zebrafish system is that large numbers of embryos can be rapidly screened for changes in cardiac structure and function. Well established, highly productive methods for mutagenesis and genetic screening or small molecule screening can be applied to fish embryos to identify in an unbiased, genome-wide approach new genes and/or pathways related to a specific phenotype3-5. This proposal brings together two productive investigators who share common interests and are dedicated to creating a collaboration in which extraordinary advances can be made. This is a new project. It entails entirely novel, potentially very powerful, and eminently feasible new studies. If funded, it will create new jobs and include purchase of new, US made equipment. The essential ingredients to fulfill the aims of the project are in place and there is a high likelihood that this work will spawn a major new research program. Finally, we believe this work exemplifies the ideals and goals of research on rare diseases. Not only is there potential for a direct positive impact on patients with a rare but deadly heart disease, but the proposed research will likely also uncover new insights into the leading cause of death in the US in a field that has long suffered from a paucity of rational therapeutic targets and strategies. PUBLIC HEALTH RELEVANCE: This project is designed to advance our understanding of sudden cardiac death, a major public health plague. We will study a rare heart disease that carries the greatest known risk of sudden death and use a novel model system to identify genetic and other factors that determine risk of sudden death. This will not only help families with the rare disease, but also people at risk of sudden death due to common forms of heart disease.