Pathogenesis of hERG Mutations in Human Long QT Syndrome
人类长 QT 综合征 hERG 突变的发病机制
基本信息
- 批准号:8452065
- 负责人:
- 金额:$ 25.04万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2001
- 资助国家:美国
- 起止时间:2001-12-05 至 2015-04-30
- 项目状态:已结题
- 来源:
- 关键词:3&apos Splice SiteAccountingAlternative SplicingArrhythmiaBerylliumC-terminalCardiacCardiac MyocytesCell LineDefectDevelopmentDiseaseDominant-Negative MutationElectrocardiogramElementsEthersExhibitsFrameshift MutationFunctional disorderFundingGene MutationGenerationsGenesGenotypeGoalsHeartHumanInitiator CodonIntronsKineticsKnowledgeLeadLengthLong QT SyndromeMediatingMessenger RNAModelingMutagenesisMutationNonsense CodonNonsense MutationOligonucleotidesPathogenesisPatientsPhenotypePlayPoly APolyadenylationPropertyProtein IsoformsProteinsRNA SplicingRegulationRelative (related person)RiskRoleRomano-Ward SyndromeSignal TransductionSplice-Site MutationSudden DeathTestingTranscriptTranslationsU1 small nuclear RNAVentricular ArrhythmiaWorkdelayed rectifier potassium channeldisease-causing mutationinduced pluripotent stem cellmRNA DecaymRNA Precursornovelnovel strategiesnovel therapeuticsprematureresearch study
项目摘要
DESCRIPTION (provided by applicant): Long QT syndrome (LQTS) is a disorder characterized by delayed cardiac repolarization and an increased risk of arrhythmias and sudden death. Long QT syndrome type 2 (LQT2) is caused by mutations in the human ether-a-go-go-related gene (hERG). hERG encodes the pore-forming subunit of the rapidly activating delayed rectifier potassium channel in the heart. LQT2 is the second most prevalent form of LQTS, accounting for 35% to 40% of genotyped cases of LQTS. LQT2 mutations can cause hERG channel dysfunction by a variety of mechanisms. In the previous funding period, we have shown that nonsense-mediated mRNA decay and splicing defects are important mechanisms of hERG channel dysfunction in LQT2. We have also shown that generation of hERG C-terminal isoforms is determined by competition between alternative splicing and polyadenylation of hERG intron 9 and that the relative expression of hERG C-terminal isoforms plays an important role in regulation of hERG channel function. In the present application, we will use full-length hERG gene constructs to study mechanisms that underlie the regulation of hERG C-terminal isoform expression, characterize two new mechanisms of hERG channel dysfunction in LQT2, and develop a novel approach to modulate the relative expression of hERG C-terminal isoforms. In addition, we will use patient-specific induced pluripotent stem (iPS) cell-derived cardiomyocytes as a model to study pathophysiology of LQT2. The specific aims of this application are: Aim 1) To study a newly identified LQT2 splice site mutation that disrupts the 3' splice site of intron 9 and alters the relative expression of hERG C-terminal isoforms. Aim 2) To develop an antisense approach to increase hERG current by inducing a shift in hERG C-terminal isoform expression from the nonfunctional isoform to the functional isoform. Aim 3) To characterize a new mechanism of LQT2 in which premature termination followed by the reinitiation of translation results in the generation of N-terminally truncated hERG channels with altered gating properties. Aim 4) To create LQT2 patient-specific iPS cell lines and characterize LQT2 mutations in iPS cell-derived cardiomyocytes. This study will increase our knowledge of how LQT2 mutations lead to hERG channel dysfunction at the posttranscriptional and translational level. We believe that this work will have a sustained and significant impact on our understanding and treatment of long QT syndrome.
描述(由申请人提供):长QT综合征(LQTS)是一种以心脏复极延迟和心律失常和猝死风险增加为特征的疾病。长QT综合征2型(LQT 2)是由人类ether-a-go-go相关基因(hERG)突变引起的。hERG编码心脏中快速激活延迟整流钾通道的成孔亚基。LQT 2是LQTS的第二大流行形式,占LQTS基因分型病例的35%至40%。LQT 2突变可通过多种机制引起hERG通道功能障碍。在之前的资助期间,我们已经证明无义介导的mRNA衰变和剪接缺陷是LQT 2中hERG通道功能障碍的重要机制。我们还表明,hERG C-末端亚型的产生是由hERG内含子9的选择性剪接和多聚腺苷酸化之间的竞争决定的,并且hERG C-末端亚型的相对表达在调节hERG通道功能中起着重要作用。在本申请中,我们将使用全长hERG基因构建体来研究hERG C-末端亚型表达调节的基础机制,表征LQT 2中hERG通道功能障碍的两种新机制,并开发一种调节hERG C-末端亚型相对表达的新方法。此外,我们将使用患者特异性诱导多能干(iPS)细胞衍生的心肌细胞作为模型来研究LQT 2的病理生理学。本申请的具体目的是:目的1)研究新鉴定的LQT 2剪接位点突变,其破坏内含子9的3'剪接位点并改变hERG C-末端同种型的相对表达。目的2)建立一种通过诱导hERG C端亚型表达由非功能性亚型向功能性亚型转变来增加hERG电流的反义方法。目的3)研究LQT 2的一种新机制,即LQT 2的翻译提前终止,随后翻译重新启动,导致产生N端截短的hERG通道,并改变其门控特性。目的4)建立LQT 2患者特异性iPS细胞系并表征iPS细胞衍生的心肌细胞中的LQT 2突变。这项研究将增加我们对LQT 2突变如何在转录后和翻译水平导致hERG通道功能障碍的认识。我们相信这项工作将对我们对长QT综合征的理解和治疗产生持续而重大的影响。
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(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
ZHENGFENG ZHOU其他文献
ZHENGFENG ZHOU的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('ZHENGFENG ZHOU', 18)}}的其他基金
Post-transcriptional regulation of Kv11.1 (hERG) channel expression by alternative splicing and polyadenylation
通过选择性剪接和多聚腺苷酸化对 Kv11.1 (hERG) 通道表达进行转录后调控
- 批准号:
10626127 - 财政年份:2022
- 资助金额:
$ 25.04万 - 项目类别:
Post-transcriptional regulation of Kv11.1 (hERG) channel expression by alternative splicing and polyadenylation
通过选择性剪接和多聚腺苷酸化对 Kv11.1 (hERG) 通道表达进行转录后调控
- 批准号:
10442308 - 财政年份:2022
- 资助金额:
$ 25.04万 - 项目类别:
Pathogenesis of hERG Mutations in Human Long QT Syndrome
人类长 QT 综合征 hERG 突变的发病机制
- 批准号:
7229524 - 财政年份:2001
- 资助金额:
$ 25.04万 - 项目类别:
Pathogenesis of HERG Mutations in Human Long QT Syndrome
人类长 QT 综合征中 HERG 突变的发病机制
- 批准号:
6683227 - 财政年份:2001
- 资助金额:
$ 25.04万 - 项目类别:
Pathogenesis of hERG Mutations in Human Long QT Syndrome
人类长 QT 综合征 hERG 突变的发病机制
- 批准号:
7624367 - 财政年份:2001
- 资助金额:
$ 25.04万 - 项目类别:
Pathogenesis of hERG Mutations in Human Long QT Syndrome
人类长 QT 综合征 hERG 突变的发病机制
- 批准号:
8302318 - 财政年份:2001
- 资助金额:
$ 25.04万 - 项目类别:
Pathogenesis of hERG Mutations in Human Long QT Syndrome
人类长 QT 综合征 hERG 突变的发病机制
- 批准号:
7844826 - 财政年份:2001
- 资助金额:
$ 25.04万 - 项目类别:
Pathogenesis of hERG Mutations in Human Long QT Syndrome
人类长 QT 综合征 hERG 突变的发病机制
- 批准号:
8961627 - 财政年份:2001
- 资助金额:
$ 25.04万 - 项目类别:
Pathogenesis of hERG Mutations in Human Long QT Syndrome
人类长 QT 综合征 hERG 突变的发病机制
- 批准号:
9243297 - 财政年份:2001
- 资助金额:
$ 25.04万 - 项目类别:
Pathogenesis of HERG Mutations in Human Long QT Syndrome
人类长 QT 综合征中 HERG 突变的发病机制
- 批准号:
6421525 - 财政年份:2001
- 资助金额:
$ 25.04万 - 项目类别:
相似海外基金
Mechanisms of Splice Site Selection in Health and Disease
健康和疾病中剪接位点选择的机制
- 批准号:
10797554 - 财政年份:2023
- 资助金额:
$ 25.04万 - 项目类别:
Quantitative and Predictive Analysis of 5' Splice Site Recognition by U1 snRNP using Massively Parallel Arrays
使用大规模并行阵列对 U1 snRNP 5 剪接位点识别进行定量和预测分析
- 批准号:
10460136 - 财政年份:2021
- 资助金额:
$ 25.04万 - 项目类别:
Quantitative and Predictive Analysis of 5' Splice Site Recognition by U1 snRNP using Massively Parallel Arrays
使用大规模并行阵列对 U1 snRNP 5 剪接位点识别进行定量和预测分析
- 批准号:
10311645 - 财政年份:2021
- 资助金额:
$ 25.04万 - 项目类别:
Uncovering Mechanisms of 5' Splice Site Fidelity
揭示 5 剪接位点保真度的机制
- 批准号:
10532793 - 财政年份:2020
- 资助金额:
$ 25.04万 - 项目类别:
How do RNA-binding proteins control splice site selection?
RNA 结合蛋白如何控制剪接位点选择?
- 批准号:
BB/T000627/1 - 财政年份:2020
- 资助金额:
$ 25.04万 - 项目类别:
Research Grant
Mechanism of Splice Site Recognition by the U2AF/SF1 Protein Complex
U2AF/SF1 蛋白复合物的剪接位点识别机制
- 批准号:
553974-2020 - 财政年份:2020
- 资助金额:
$ 25.04万 - 项目类别:
Alexander Graham Bell Canada Graduate Scholarships - Master's
Uncovering Mechanisms of 5' Splice Site Fidelity
揭示 5 剪接位点保真度的机制
- 批准号:
10316181 - 财政年份:2020
- 资助金额:
$ 25.04万 - 项目类别:
Mechanisms of Splice Site Selection in Health and Disease
健康和疾病中剪接位点选择的机制
- 批准号:
10769989 - 财政年份:2019
- 资助金额:
$ 25.04万 - 项目类别:
Mechanisms of Splice Site Selection in Health and Disease
健康和疾病中剪接位点选择的机制
- 批准号:
10808389 - 财政年份:2019
- 资助金额:
$ 25.04万 - 项目类别:
Mechanisms of Splice Site Selection in Health and Disease
健康和疾病中剪接位点选择的机制
- 批准号:
10585911 - 财政年份:2019
- 资助金额:
$ 25.04万 - 项目类别: