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:
    8489335
  • 负责人:
  • 金额:
    $ 39.74万
  • 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 2015-06-30
  • 项目状态:
    已结题

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.
描述(由申请人提供):先天性长QT综合征(LQTS)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。LQTS影响1/3000的个体,每年导致约4,000人死亡。虽然我们对LQTS的分子发病机制的理解已经取得了重大进展,但治疗选择仍然有限。药物治疗的支柱仍然是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,这是侵入性的,并且具有显著的短期和长期风险,包括不适当的电击和感染。由于LQT患者通常在就诊时很年轻,因此他们承受多次ICD发生器更换和电极导线翻修的风险和发病率。 心脏复极的显著种间差异在LQTS动物模型的识别中产生了显著的障碍。在过去的几年里,我们的实验室为斑马鱼心脏电生理模型的发展做出了贡献。使用这个模型,我们已经证明了复极的遗传和化学扰动的忠实再现。斑马鱼突变体霹雳舞携带钾通道基因KCNH 2的突变,KCNH 2是人类长QT 2型(LQT 2)中突变的基因。2型LQTS占所有人类长QT病例的约三分之一。KCNH 2编码通道也是迄今为止发现的每种QT延长药物的靶点。在初步的数据中,我们表明,斑马鱼霹雳舞突变概括了人类长QT 2综合征的几个关键特征。霹雳舞突变I59 S导致蛋白质不经历复杂的糖基化或运输到质膜,类似于迄今为止研究的大多数人类LQT 2病例。在1200个小分子的手动中试筛选中,我们已经确定了两种抑制斑马鱼LQT 2表型的化合物。在二次筛选中,我们证明了这些化合物缩短了我们的LQT 2模型中的心室动作电位时程。这些来自小型手动试验筛选的初步结果支持大规模筛选工作。在本提案中,我们详细说明了自动化斑马鱼LQT测定的计划,以鉴定抑制斑马鱼长QT表型的小分子,具体目的如下:1.建立一种检测斑马鱼LQT表型的自动化方法。2.使用斑马鱼LQT模型来检验整个生物体HTS可行的假设。 心脏电生理学的生物学复杂性以及长QT综合征中缺乏经验证的药物靶点需要在完整的生物体中进行筛选。本申请中描述的测定将是用于发现小分子和治疗靶点的独特工具,所述小分子和治疗靶点特异性地解决LQTS中的潜在生理缺陷,服务于尚未满足的临床需求。

项目成果

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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

Novel Therapy for Long QT Syndrome
长 QT 综合征的新疗法
  • 批准号:
    9152955
  • 财政年份:
    2016
  • 资助金额:
    $ 39.74万
  • 项目类别:
Genetics and Mechanisms of Mitral Valve Prolapse
二尖瓣脱垂的遗传学和机制
  • 批准号:
    9258482
  • 财政年份:
    2015
  • 资助金额:
    $ 39.74万
  • 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
  • 批准号:
    8154017
  • 财政年份:
    2011
  • 资助金额:
    $ 39.74万
  • 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
  • 批准号:
    8328584
  • 财政年份:
    2011
  • 资助金额:
    $ 39.74万
  • 项目类别:
Electrical Silencing of the Pulmonary Veins
肺静脉电沉默
  • 批准号:
    7787967
  • 财政年份:
    2010
  • 资助金额:
    $ 39.74万
  • 项目类别:
Electrical Silencing of the Pulmonary Veins
肺静脉电沉默
  • 批准号:
    8020040
  • 财政年份:
    2010
  • 资助金额:
    $ 39.74万
  • 项目类别:
The Genetic Basis of Novel Loci Influencing Myocardial Repolarization
影响心肌复极的新位点的遗传基础
  • 批准号:
    7708608
  • 财政年份:
    2009
  • 资助金额:
    $ 39.74万
  • 项目类别:
A Molecular Study of Cardiac Repolarization
心脏复极的分子研究
  • 批准号:
    7169878
  • 财政年份:
    2005
  • 资助金额:
    $ 39.74万
  • 项目类别:
A Molecular Study of Cardiac Repolarization
心脏复极的分子研究
  • 批准号:
    7339296
  • 财政年份:
    2005
  • 资助金额:
    $ 39.74万
  • 项目类别:
A Molecular Study of Cardiac Repolarization in Zebrafish
斑马鱼心脏复极的分子研究
  • 批准号:
    7008583
  • 财政年份:
    2005
  • 资助金额:
    $ 39.74万
  • 项目类别:

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