Determinants of Disease Expression in Arrhythmogenic Cardiomyopathy

致心律失常性心肌病疾病表达的决定因素

• 批准号: 7826249
• 负责人: JEFFREY E SAFFITZ
• 金额: $ 50万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7826249
• 关键词: Accounting; Address; Affect; Age; Applications Grants; Area; Arrhythmia; Arrhythmogenic Right Ventricular Dysplasia; Biological; Biological Assay; Biological Models; Biology; Cardiac; Cardiac Myocytes; Cardiomyopathies; Cause of Death; Cellular Structures; Chemicals; Classification; Collaborations; Defibrillators; Development; Diagnosis; Disease; Dominant-Negative Mutation; Drug usage; Early Diagnosis; Electrophysiology (science); Embryo; Ensure; Equipment; Evaluation; FDA approved; Familial disease; Family; First Degree Relative; Fishes; Functional disorder; Funding; Future; Genes; Genetic; Genetic Models; Genetic Screening; Goals; Heart; Heart Diseases; Human; In Vitro; Incidence; Individual; Inherited; Ions; Libraries; Methods; Modeling; Molecular Profiling; Morbidity - disease rate; Mutation; Myocardial; Myocardial tissue; Myocardium; Myopathy; Occupations; Other Genetics; Pathway interactions; Patients; Penetrance; Pharmaceutical Preparations; Phenotype; Physiological; Pilot Projects; Plague; Prevention; Property; Proteins; Public Health; Quality of life; Rare Diseases; Receptor Signaling; Research; Research Personnel; Risk; Role; Screening procedure; Shock; Signal Transduction; Staging; Structure; Sudden Death; System; Tachyarrhythmias; Testing; Transgenic Organisms; Translational Research; Ventricular; Work; Zebrafish; base; chemical genetics; design; desmocollin; desmoglein; desmoplakin; disease-causing mutation; effective therapy; experience; genome-wide; high throughput screening; human disease; in vivo; in vivo Model; indexing; insight; interest; mutant; novel; novel strategies; plakoglobin; plakophilins; programs; public health relevance; small molecule; sudden cardiac death; therapeutic target

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.

描述（由申请人提供）： 该申请涉及广泛的挑战领域（15）转化研究和特定的挑战主题15-OD（ORR）-101：预防，早期发现和治疗罕见疾病的试点项目。这项挑战补助金申请的重点是致心律失常性右心室心肌病（ARVC），一种罕见的原发性心肌疾病，其特征是严重室性快速性心律失常和心源性猝死的发生率很高，通常发生在收缩功能障碍和心脏重塑的发展之前1，2。它是人类心脏病中最易引起心脏病的形式。ARVC患者的适当ICD电击率大大超过其他心肌病和离子通道病。因此，了解ARVC中心脏病发生的潜在决定因素可能为更常见的心脏病形式的猝死机制提供新的见解。ARVC是家族性疾病。编码桥粒蛋白（桥粒芯蛋白，桥粒胶原蛋白，桥粒斑蛋白，斑珠蛋白，斑嗜蛋白）的一个或多个基因的突变可以在至少40%的受影响的个体中鉴定1，2。到目前为止，在编码与桥粒蛋白的结构和信号作用相关的蛋白质的其他基因中尚未发现的突变可能是许多（如果不是全部的话）剩余病例的原因。与其他家族性非缺血性心肌病相比，ARVC的特点是遗传变异和疾病表现的变异性更大1。在同一个家庭中，携带相同致病突变的个体，其疾病表现却截然不同，这并不罕见。索引病例可能会在年轻时发生心脏性猝死，而具有相同突变的一级亲属可能会完全正常并存活到老年。这表明，强大的修饰剂起作用，以确定疾病的表达和猝死的风险。然而，实际上对这些修饰符一无所知。此外，ARVC的唯一有效治疗方法是植入式心脏除颤器，虽然可能挽救生命，但价格昂贵，并且可能对发病率和生活质量产生重大影响。确定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。在这项挑战资助申请中，我们建议使用斑马鱼作为模型系统，以发现ARVC中的肿瘤发生和疾病表达的决定因素。虽然鱼有两个心室的心脏，相同的基本生物学原理，发育途径，基因表达谱，细胞结构和功能特性适用于鱼类和人类的心肌细胞和心肌组织3。几乎所有用于治疗心脏病患者的主要药物都在斑马鱼心脏中具有同源受体、信号级联和生理效应。斑马鱼系统的巨大优势在于，可以快速筛选大量胚胎的心脏结构和功能变化。用于诱变和遗传筛选或小分子筛选的成熟、高产的方法可应用于鱼胚胎，以无偏倚的全基因组方法鉴定与特定表型相关的新基因和/或途径3 -5。这一提议汇集了两个富有成效的调查人员，他们有着共同的兴趣，并致力于建立一个可以取得非凡进步的合作。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。如果获得资助，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，这项工作很有可能产生一个重大的新研究计划。最后，我们相信这项工作阐明了罕见疾病研究的理想和目标。不仅有可能对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揭示美国主要死亡原因的新见解，该领域长期以来一直缺乏合理的治疗目标和策略。 公共卫生相关性：该项目旨在促进我们对心脏性猝死的理解，这是一种主要的公共卫生瘟疫。我们将研究一种罕见的心脏病，它具有最大的已知猝死风险，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。这不仅可以帮助患有这种罕见疾病的家庭，还可以帮助那些因常见心脏病而面临猝死风险的人。