Genetics and Mechanisms of Mitral Valve Prolapse
二尖瓣脱垂的遗传学和机制
基本信息
- 批准号:9258482
- 负责人:
- 金额:$ 75.88万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2015
- 资助国家:美国
- 起止时间:2015-04-01 至 2019-02-28
- 项目状态:已结题
- 来源:
- 关键词:AdultAffectAffinityAmericanBinding ProteinsCalcineurinCandidate Disease GeneCardiac Surgery proceduresCell PolarityCell ProliferationChildhoodChromosomesClinical TreatmentCongestive Heart FailureCysteine-Rich DomainDNADataData SetDefectDevelopmentDiagnosticDiseaseDrosophila genusEmbryoEndocarditisFBN1Functional disorderFundingGeneral HospitalsGenesGeneticGenetic Predisposition to DiseaseGenetic studyGoalsGrowthHalf-LifeHeart DiseasesHeart ValvesHeritabilityHumanImpairmentIn VitroIntegrinsInvestigationKnockout MiceLaboratoriesLeadLengthLinkMarfan SyndromeMassachusettsMedicalMedicineMicrofilamentsMitral ValveMitral Valve InsufficiencyMitral Valve ProlapseModelingMolecular AbnormalityMorbidity - disease rateMusMutationNeurologyOnset of illnessOperative Surgical ProceduresPathogenesisPathway interactionsPhenotypePlayPopulationPreventionProteinsProteomicsPtosisPublishingResearch PersonnelRiskRoleSeminalShapesSignal TransductionSouth CarolinaStem cellsThickUniversitiesWorkZebrafishcase controlcell growthcell motilitycohortcommon treatmentdrug discoveryfilamingenetic variantgenome wide association studygenome-wideknock-downmortalitymouse modelmutantnew therapeutic targetnovelpreventprofessorpublic health relevancetensin
项目摘要
DESCRIPTION (provided by applicant): Mitral valve prolapse (MVP) affects 2.4% of the population and results in more than 7,000 open heart surgeries each year in the US alone. MVP is characterized by excessive valve leaflet growth resulting in prolapse, impaired valve closure and mitral regurgitation (MR), which can cause serious complications including endocarditis and congestive heart failure. Fibrillin-1 mutations cause MVP in Marfan syndrome and Filamin A mutations cause an X-linked form of pan-valvular myxomatous dystrophy, but to date, despite a clear heritable component, no genes have been identified for non-syndromic MVP. However, we now have compelling, soon to be published data from two approaches that significantly advance our understanding of the genetics of MVP. First, we have identified mutations in Dachsous 1 (DCHS1) as a cause of MVP. DCHS1 was discovered in Drosophila and plays an important role in cell growth and polarity. Knockdown of zebrafish dchs1 resulted in atrioventricular regurgitation that could not be rescued by the mutant human protein. In vitro studies of mutant and wild type forms of human DCHS1 revealed reduced half-life of the mutant protein. Finally the haploinsufficient Dchs1 mouse displays classic MVP with altered leaflet length and thickness and functional prolapse. These results confirm a role for DCHS1 in mitral valve disease. Second, we recently completed a genome wide association study (GWAS) to identify common genetic variants associated with MVP. Using a population of 2,854 cases we identified 6 novel genetic loci that reached genome wide significance and replicated in independent cohorts. In order to identify causal genes we knocked down candidate genes from three loci in zebrafish, identifying two genes that cause a valve phenotype: Tensin 1, (TNS1) an integrin and actin filament binding protein, and LIM and cysteine-rich domains 1 (LMCD1), which augments calcineurin/NFAT signaling. These genes are excellent functional candidates for MVP. Our exciting preliminary data set the stage for mechanistic investigation into the pathogenesis of MVP. Our hypothesis is that the newly identified genes regulate cell migration during development which, when perturbed, results in MVP. Specifically, we aim to: 1.Expand the network of MVP genes by: a. evaluating the remaining GWAS loci, b. performing comprehensive protein interaction studies using affinity proteomics, and c. explore the role of the MVP gene network in regulating cellular migration, 2. Investigate the mechanism of valve dysfunction in Tns1 knockout mice, and 3. Determine the burden of mutations in MVP genes by performing DNA capture and sequencing in a large case-control cohort. Mitral valve prolapse is a cause of significant morbidity and mortality. There are currently no treatments short of surgery, in part because the pathogenesis is poorly understood. Given these challenges, we believe that our work on the newly discovered MVP genes will facilitate a greater understanding of MVP and may ultimately provide novel targets for prevention and treatment of this common and clinically important disease.
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)
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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
High Throughput Screening for Chemical Modifiers of Long QT Syndrome
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- 批准号:
8154017 - 财政年份:2011
- 资助金额:
$ 75.88万 - 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:
$ 75.88万 - 项目类别:
High Throughput Screening for Chemical Modifiers of Long QT Syndrome
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8489335 - 财政年份:2011
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$ 75.88万 - 项目类别:
The Genetic Basis of Novel Loci Influencing Myocardial Repolarization
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7008583 - 财政年份:2005
- 资助金额:
$ 75.88万 - 项目类别:
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