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）： 该应用程序解决了广泛的挑战领域 (15) 转化研究和特定挑战主题 15-OD(ORDR)-101：罕见疾病预防、早期检测和治疗的试点项目。该挑战拨款申请的重点是致心律失常性右心室心肌病 (ARVC)，这是一种罕见的原发性心肌疾病，其特征是严重室性快速心律失常和心源性猝死的发生率高，通常先于收缩功能障碍和心脏重塑1, 2。它是人类心脏病中最致心律失常的形式。 ARVC 患者接受适当 ICD 电击的比例大大超过其他心肌病和离子通道病患者。因此，了解 ARVC 心律失常发生的根本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 是一种家族性疾病。至少 40% 的受影响个体1、2 中可以鉴定出一种或多种编码桥粒蛋白（桥粒糖蛋白、桥粒胶蛋白、桥粒斑蛋白、斑球蛋白、亲斑蛋白）的基因突变。迄今为止，编码与桥粒蛋白的结构和信号传导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）的原因。 其余案件。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变异性更大1。对于同一家庭中具有相同致病突变的个体来说，具有显着不同的疾病表现并不罕见。指示病例可能在年轻时经历心源性猝死，而具有相同突变的一级亲属可能看起来完全正常并存活到老年。这表明强大的修饰因素可以决定疾病的表达和猝死的风险。然而，人们对这些修饰符几乎一无所知。此外，ARVC 唯一有效的治疗方法是植入式心脏除颤器，虽然它可能挽救生命，但价格昂贵，并且可能对发病率和生活质量产生重大影响。鉴定 ARVC 中疾病表达的决定因素可以提供新的基于机制的疗法1, 2。在本次挑战拨款申请中，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。尽管鱼有两腔心脏，但鱼和人类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心脏中都具有同源受体、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类胚胎，以公正的全基因组方法识别与特定表型相关的新基因和/或途径3-5。该提案汇集了两位富有成效的研究人员，他们有着共同的兴趣，并致力于建立一种可以取得非凡进展的合作。这是一个新项目。它需要全新的、可能非常强大且非常可行的新研究。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，这项工作很可能会催生一个重大的新研究计划。最后，我们相信这项工作体现了罕见疾病研究的理想和目标。这项研究不仅可能对患有罕见但致命的心脏病的患者产生直接的积极影响，而且还可能对美国这一长期缺乏合理治疗目标和策略的领域的主要死亡原因揭示新的见解。 公共卫生相关性：该项目旨在增进我们对心源性猝死这一重大公共卫生瘟疫的了解。我们将研究一种罕见的心脏病，这种疾病具有最大的已知猝死风险，并使用一种新颖的模型系统来识别遗传和其他决定猝死风险的因素。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。