High Throughput Screening for Chemical Modifiers of Long QT Syndrome
高通量筛选长 QT 综合征的化学修饰剂
基本信息
- 批准号:8154017
- 负责人:
- 金额:$ 62.35万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2011
- 资助国家:美国
- 起止时间:2011-09-05 至 2014-06-30
- 项目状态:已结题
- 来源:
- 关键词:Action PotentialsAddressAffectAnimal ModelArrhythmiaAutomationBiological AssayCardiacCase StudyCell membraneCellsCessation of lifeChemical ModifierChemicalsClinicalComplementComplexDancingDataDefectDetectionDevelopmentDiseaseDrug Delivery SystemsElectrocardiogramElectrophysiology (science)EnvironmentGenesGeneticHeart RateHereditary DiseaseHumanImplantable DefibrillatorsIn VitroIndividualInfectionLaboratoriesLeadLifeLong QT SyndromeManualsModelingMolecularMolecular TargetMorbidity - disease rateMutateMutationOrganismPathogenesisPatientsPharmaceutical PreparationsPhenotypePhysiologicalPotassium ChannelProcessPropertyProteinsRegulationReproductionRiskScreening procedureShockSyndromeTestingTherapeuticToxic effectUrsidae FamilyVariantVentricularWhole OrganismZebrafishassay developmentbasechemical geneticsglycosylationhigh throughput screeningmutantresponsesmall moleculesudden cardiac deaththerapeutic targettooltrafficking
项目摘要
DESCRIPTION (provided by applicant): Congenital long QT syndrome (LQTS) is a heritable disease that carries an increased risk of sudden cardiac death due to cardiac arrhythmia. LQTS affects 1 in 3000 individuals and results in approximately 4,000 deaths annually. While significant advances have been made in our understanding of the molecular pathogenesis of LQTS, treatment options remain limited. The mainstay of pharmacologic therapy remains beta-blockade, which often provides incomplete and unreliable protection against life-threatening arrhythmias. Thus, many patients require implantable cardioverter defibrillators which are invasive, and carry significant short and long-term risks including inappropriate shocks and infection. Because LQT patients are often young at presentation they bear the risk and morbidity of multiple ICD generator changes and lead revisions. Marked interspecies variation in cardiac repolarization has created significant barriers in identification of animal models of LQTS. Over the last several years, our laboratory has contributed to the development of a zebrafish model of cardiac electrophysiology. Using this model we have demonstrated the faithful reproduction of both genetic and chemical perturbations of repolarization. The zebrafish mutant break-dance carries a mutation in the potassium channel gene, KCNH2, which is the gene mutated in human long QT type 2 (LQT2). Type 2 LQTS is responsible for approximately one third of all human long QT cases. The KCNH2 encoded channel is also the target of every QT prolonging drug identified to date. In preliminary data we show that the zebrafish break-dance mutant recapitulates several key features of human long QT2 syndrome. The break-dance mutation, I59S, results in a protein that does not undergo complex glycosylation or trafficking to the plasma membrane, similar to the majority of human LQT2 cases studied to date. In a manual pilot screen of 1200 small molecules, we have identified two compounds that suppress the zebrafish LQT2 phenotype. In a secondary screen, we demonstrate that these compounds shorten the ventricular action potential duration in our LQT2 model. These preliminary results from a small manual pilot screen support a large scale screening effort. In this proposal we detail plans to automate our zebrafish LQT assay in order to identify small molecules that suppress the zebrafish long QT phenotype in the following Specific Aims: 1. To develop an automated assay for detection of the zebrafish LQT phenotype. 2. To test the hypothesis that whole-organism HTS is feasible using the zebrafish LQT model. The biologic complexity of cardiac electrophysiology as well as the lack of validated drug targets in Long QT Syndrome demands screening in an intact organism. The assays described in this application will be unique tools for discovering small molecules and therapeutic targets that specifically address the underlying physiologic defect in LQTS, serving an as yet unmet clinical need.
PUBLIC HEALTH RELEVANCE: Congenital long QT syndrome is a genetic disease that carries an increased risk of sudden cardiac death due to cardiac arrhythmia and for which current therapies are inadequate. In this proposal we detail plans to automate a zebrafish assay of long QT syndrome in order to identify new compounds that could be used to treat this disease. The studies described in this application will provide unique tools for discovering small molecules and therapeutic targets that specifically address the underlying problem in LQTS, serving an as yet unmet clinical need.
描述(申请人提供):先天性QT间期延长综合征(LQTS)是一种遗传性疾病,由于心律失常而导致心脏性猝死的风险增加。LQTS每年影响3000人中的1人,并导致约4000人死亡。虽然我们对LQTS的分子发病机制的了解已经取得了重大进展,但治疗选择仍然有限。药物治疗的主流仍然是β-受体阻滞剂,它通常对危及生命的心律失常提供不完全和不可靠的保护。因此,许多患者需要植入式心律转复除颤器,这种除颤器具有侵入性,并具有重大的短期和长期风险,包括不适当的休克和感染。由于LQT患者在发病时通常很年轻,他们承担了多个ICD发生器改变和导联翻修的风险和发病率。心脏复极的显著种间差异给LQTS动物模型的识别造成了巨大的障碍。在过去的几年里,我们的实验室为斑马鱼心脏电生理学模型的发展做出了贡献。利用这个模型,我们已经证明了复极化的遗传和化学微扰的忠实再现。斑马鱼突变的霹雳舞携带钾通道基因KCNH2的突变,该基因在人类长QT2型(LQT2)中发生突变。2型LQTS约占人类长QT间期病例的三分之一。KCNH2编码通道也是迄今发现的每一种延长QT的药物的靶点。在初步数据中,我们表明斑马鱼霹雳舞突变体概括了人类长QT2综合征的几个关键特征。这种突变式突变I59S导致一种蛋白质不经历复杂的糖基化或运输到质膜,类似于迄今研究的大多数人类LQT2病例。在1200个小分子的人工筛选中,我们已经确定了两个抑制斑马鱼LQT2表型的化合物。在二次筛选中,我们证明了在我们的LQT2模型中,这些化合物缩短了心室动作电位时程。这些来自小型手动飞行员筛查的初步结果支持大规模筛查工作。在这项提案中,我们详细介绍了自动化斑马鱼LQT检测的计划,以便在以下特定目标中识别抑制斑马鱼长QT表型的小分子:1.建立一种检测斑马鱼LQT表型的自动化检测方法。2.利用斑马鱼LQT模型验证整体高温超导的可行性。心脏电生理学的生物学复杂性,以及长QT间期综合征缺乏有效的药物靶点,需要在完整的生物体中进行筛选。本申请中描述的分析将是发现小分子和治疗靶点的独特工具,这些小分子和治疗靶点专门解决LQTS的潜在生理缺陷,服务于尚未满足的临床需求。
公共卫生相关性:先天性QT间期延长综合征是一种遗传性疾病,由于心律失常导致心源性猝死的风险增加,目前的治疗方法不足以治疗这种疾病。在这项提案中,我们详细介绍了实现长QT综合征斑马鱼检测自动化的计划,以确定可用于治疗这种疾病的新化合物。本申请中描述的研究将为发现小分子和治疗靶点提供独特的工具,这些小分子和治疗靶点专门解决LQTS的潜在问题,服务于尚未满足的临床需求。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(1)
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David J Milan其他文献
David J Milan的其他文献
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{{ truncateString('David J Milan', 18)}}的其他基金
Genetics and Mechanisms of Mitral Valve Prolapse
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$ 62.35万 - 项目类别:
High Throughput Screening for Chemical Modifiers of Long QT Syndrome
高通量筛选长 QT 综合征的化学修饰剂
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8328584 - 财政年份:2011
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$ 62.35万 - 项目类别:
High Throughput Screening for Chemical Modifiers of Long QT Syndrome
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