Molecular and genetic mechanisms of cardiac conduction development and disease

心脏传导发育和疾病的分子和遗传机制

• 批准号: 8282696
• 负责人: Neil C Chi
• 金额: $ 38.75万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8282696
• 关键词: Adult; Affect; Arrhythmia; Behavior; Cardiac; Cardiac Myocytes; Cardiac conduction system; Cells; Cessation of life; Collection; Complex; Connexins; Data; Defect; Development; Diagnosis; Disease; Environment; Environmental Risk Factor; Event; Exhibits; Fishes; Genes; Genetic; Genetic Screening; Genomics; Heart; Heart failure; Human; Individual; Intercellular Junctions; Lead; Link; Long QT Syndrome; Mammals; Maps; Modeling; Molecular; Molecular Genetics; Mus; Mutation; Optics; Organism; Orthologous Gene; Patients; Phenotype; Physiological; Play; Regulation; Rewards; Role; Syndrome; System; Testing; Therapeutic; Transgenic Organisms; United States; Ventricular; Ventricular Arrhythmia; Work; Zebrafish; base; cardiogenesis; heart function; human disease; improved; in vivo; innovation; insight; intercellular communication; loss of function; man; mutant; novel; outcome forecast; sudden cardiac death; tool; trafficking

DESCRIPTION (provided by applicant): Every year, approximately 450,000 individuals in the United States die suddenly of cardiac arrhythmias due to disorganized ventricular conduction, with many of these deaths linked to both genetic and environmental factors. However, the identification of these genetic factors and how they work alone, together, or in concert with the environment to modulate the cellular and molecular behavior leading to arrhythmic events is far from complete. Thus, studies which identify novel genetic factors linked to cardiac arrhythmias may aid in diagnosis and treatment of patients predisposed for cardiac arrhythmias. The zebrafish has proven to be an outstanding model for understanding human diseases since it has morphologic and physiologic similarities to mammals, and provides an organism with an array of genomic tools which facilitates large-scale phenotype- based screens. For instance, there are zebrafish mutants whose phenotypes resemble complex human disorders, including common adult cardiac syndromes which result in heart failure and arrhythmias. In several cases, phenotypic similarity between man and fish has been confirmed by molecular definition. More recently, the creation of innovative transgenic tools has resulted in more sophisticated in vivo cellular and physiologic analysis as well as phenotypic-based screens. As a result, using a transgenic-based in vivo optical mapping system to perform a new physiologic-based forward genetic screen, we have assembled a collection of mutations that specifically affect ventricular conduction. Most notably, we have discovered that the dococ (dco) and daredevil (ddl) genes are critical regulators of organized ventricular conduction. dco encodes Gja3/Cx46, a gap junction protein not previously implicated in heart development or function, whereas ddl encodes RhoGa, a zebrafish ortholog of RhoG which may affect Cx46 trafficking. In contrast to cardiac Cx40, 43, and 45, the role of Cx46 in heart development or function remains to be further elucidated. Thus, we hypothesize that Cx46 functions in concert with cardiac Cx40, 43, and 45 to organize ventricular conduction through regulation of intercellular communication between specialized ventricular conduction system cardiomyocytes. Our specific aims are: 1) to elucidate underlying mechanisms of how Cx46 regulates ventricular conduction; 2) to determine whether Cx46 cardiac function is conserved in the mammalian cardiac conduction system, and 3) to investigate underlying mechanisms by which rhoga regulates ventricular conduction. Overall, the combination of cellular, molecular and physiologic studies proposed in this project will provide new and in-depth insight into mechanisms of human ventricular arrhythmias. These studies may prove rewarding for prognosis and diagnosis of patients susceptible to sudden cardiac death as well as for developing therapeutic options aimed at maintaining and/or improving overall cardiac conduction.

描述（由申请人提供）：每年，美国大约有450,000名因心律不齐而突然死于心律不齐，导致室心电传导混乱，其中许多死亡都与遗传和环境因素有关。但是，这些遗传因素的鉴定以及它们如何独自工作，或与环境一起调节细胞和分子行为，导致心律不齐事件远非完整。因此，鉴定与心律不齐相关的新遗传因素的研究可能有助于诊断和治疗心律不齐的患者。斑马鱼已被证明是理解人类疾病的杰出模型，因为它与哺乳动物具有形态和生理相似性，并为有机体提供了一系列基因组工具，可促进基于大规模表型的筛查。例如，有一些斑马鱼突变体的表型类似于复杂的人类疾病，包括常见的成人心脏综合征，导致心力衰竭和心律不齐。在某些情况下，分子定义证实了人与鱼之间的表型相似性。最近，创新的转基因工具的创建导致体内细胞和生理分析以及基于表型的筛选更复杂。结果，使用基于转基因的体内光学映射系统执行新的基于生理的前遗传筛选，我们组装了一系列突变，这些突变特别影响心室传导。最值得注意的是，我们发现DOCOC（DCO）和DADAREDEVIL（DDL）基因是有组织的心室传导的关键调节剂。 DCO编码GJA3/CX46，这是一种以前不涉及心脏发育或功能的间隙连接蛋白，而DDL编码Rhoga，Rhoga是RHOG的斑马鱼直立性，可能会影响CX46运输。与心脏CX40、43和45相反，CX46在心脏发育或功能中的作用仍有进一步阐明。因此，我们假设CX46与心脏CX40、43和45一起起作用，通过调节专业心室传导系统心肌细胞之间的细胞间通信来组织心室传导。我们的具体目的是：1）阐明CX46如何调节心室传导的基本机制； 2）确定CX46心脏功能是否在哺乳动物心脏传导系统中保守，3）研究Rhoga调节心室传导的基本机制。总体而言，该项目中提出的细胞，分子和生理研究的结合将提供对人心室心律不齐机理的新的深入了解。这些研究可能会证明对易感心脏死亡的患者的预后和诊断以及旨在维持和/或改善总体心脏传导的治疗方案的预后和诊断。