Elucidating the Origin of Sudden Cardiac Death in Dilated Cardiomyopathy: from Phenotype Predictors to Therapeutic Targets
阐明扩张型心肌病心脏性猝死的起源:从表型预测因子到治疗靶点
基本信息
- 批准号:10658201
- 负责人:
- 金额:$ 72.73万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-04-05 至 2028-02-29
- 项目状态:未结题
- 来源:
- 关键词:AgeArrhythmiaBasic ScienceCardiacCardiac MyocytesCardiomyopathiesCellsCirculationClinicalClinical DataClinical SciencesCohort StudiesColoradoDataDevelopmentDilated CardiomyopathyDiseaseEarly identificationEthnic OriginFLNC geneFibroblastsFibrosisFoundationsGenderGene Expression ProfileGene MutationGenesGeneticGenomicsGenotypeGoalsHeartHumanImageImplantable DefibrillatorsIndividualKnowledgeLeft Ventricular Ejection FractionLifeMalignant - descriptorModelingMolecularMorbidity - disease rateMutationMyocardial dysfunctionNational Heart, Lung, and Blood InstituteNatureOutcome MeasurePathogenicityPathway interactionsPatientsPhenotypePopulationPreventionPreventivePrognosisRegistriesReportingResearch PersonnelRiskRoleScienceSignal PathwaySignal TransductionSocietiesTissue-Specific Gene ExpressionTrans-Omics for Precision MedicineTranslatingTranslational ResearchUnited States National Institutes of HealthUniversitiesVariantVentricular ArrhythmiaWorkcardiac tissue engineeringclinical predictorscohortcoronary fibrosisdesignexperimental studyfilamingenetic predictorsgenome editinggenome sequencingheart rhythmhigh riskimplantationinduced pluripotent stem cellinduced pluripotent stem cell derived cardiomyocytesinterdisciplinary approachmortalitymortality riskmultidisciplinarymutantnext generation sequencingnovelnovel therapeutic interventionpharmacologicprecision medicinerisk predictionrisk stratificationsudden cardiac deaththerapeutic targettissue support frametooltranscriptometranscriptome sequencingwhole genome
项目摘要
Project Abstract
The molecular mechanisms and the clinical predictors of life-threatening arrhythmias in patients with dilated,
nonischemic cardiomyopathy (DCM) remain elusive, hampering adequate prevention and treatment of sudden
cardiac death (SCD) and malignant ventricular arrhythmias (VA) in this population. Our application will address
this unmet need. Our established team of investigators from the University of Colorado and Stanford University
has assembled preliminary data and proof-of-concept experiments to tackle three complementary aims, which
will comprehensively fill critical knowledge gaps in life-threatening VA and SCD risk in DCM. We hypothesize
that two main mechanisms are involved in VA/SCD in DCM: genetic factors (“arrhythmogenic” genes) and
cardiac fibrosis. We will address these hypotheses with three independent but complementary Specific Aims
(clinical, translational and mechanistic) designed to translate the discovery of mechanisms and delineation of
prognosis into a precision medicine approach. Specific Aim 1 will define genotype and phenotype
predictors of malignant VA and SCD in DCM. Our preliminary studies show that phenotype, such as
myocardial fibrosis, and gene mutations significantly increase the risk of VA/SCD. Thus, we hypothesize that a
clinical multidisciplinary approach including genotype and advanced imaging can precisely identify DCM patients
at risk of SCD. Using deep phenotyping, outcome measures, and NextGen sequencing in the Familial
Cardiomyopathy Registry (1,316 DCM subjects), we will generate a SCD risk prediction score for clinical use.
Specific Aim 2 will identify the transcriptome signature of VA. We found that explanted hearts of patients
with arrhythmogenic DCM have a distinct transcriptional signature. Thus, we hypothesize that, in advanced-
stage DCM, lethal arrhythmias are driven by genetically determined transcriptional signatures. We will leverage
whole genome and transcriptome sequencing data from our NIH/NHLBI TOPMed project (X01 HL139403: 1078
explanted hearts, 504 DCM, 140 controls) to identify gene-specific dysregulated pathways predicting high-risk
VA. Specific Aim 3 will elucidate the molecular mechanisms of arrhythmogenic genes. Our preliminary
data in mutant human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) show evidence of
intrinsic electrical instability. However, the role of cardiac fibroblasts and CM/CF cross-talk in arrhythmogenesis
remains unknown. We hypothesize that arrhythmogenic DCM genes activate fibroblasts and induce arrhythmia,
either directly or indirectly through their interaction with cardiomyocytes. hiPSC-CM and cardiac fibroblasts
(hiPSC-CF) will be generated from 60 patients from our Registry (Aim 1) and genome edited models with
mutations in arrhythmogenic genes (LMNA, FLNC, DSP), and 20 age/gender/ethnicity-matched healthy
individuals. Using engineered heart tissue scaffolds (EHT), we will elucidate the mechanisms of CFs activation
and arrhythmia, compare altered signaling pathways in iPSC-derived models with those in the explanted hearts
cohort (Aim 2), and pharmacologically rescue the phenotype.
项目摘要
扩张型心绞痛患者危及生命的心律失常的分子机制和临床预测因素,
非缺血性心肌病(DCM)仍然难以捉摸,阻碍了对突发性心肌病的充分预防和治疗。
心源性死亡(SCD)和恶性室性心律失常(VA)。我们的应用程序将解决
这种未满足的需求。我们成立的研究团队来自科罗拉多大学和斯坦福大学
已经收集了初步数据和概念验证实验,以解决三个互补的目标,
将全面填补DCM中危及生命的VA和SCD风险的关键知识空白。我们假设
DCM中VA/SCD涉及两种主要机制:遗传因素(“致瘤”基因)和
心脏纤维化我们将通过三个独立但互补的具体目标来解决这些假设
(临床、转化和机制)旨在转化机制的发现和
将预后转化为精准医疗。具体目标1将定义基因型和表型
DCM中恶性VA和SCD的预测因子。我们的初步研究表明,表型,如
心肌纤维化和基因突变显著增加VA/SCD的风险。因此,我们假设,
临床多学科方法,包括基因分型和先进的影像学可以精确地识别DCM患者
有SCD的风险。使用深度表型分析、结果测量和NextGen测序在家族性
心肌病登记研究(1,316名DCM受试者),我们将生成供临床使用的SCD风险预测评分。
Specific Aim 2将识别VA的转录组特征。我们发现病人的心脏
具有独特的转录特征。我们假设,在未来,
在DCM阶段,致命性心律失常由遗传决定的转录特征驱动。我们将利用
来自我们的NIH/NHLBI TOPMed项目的全基因组和转录组测序数据(X 01 HL 139403:1078
心脏移植,504例DCM,140例对照),以确定预测高风险的基因特异性失调途径。
弗吉尼亚具体目标3将阐明致瘤基因的分子机制。我们的初步
在突变的人诱导多能干细胞衍生的心肌细胞(hiPSC-CM)中的数据显示,
内在电不稳定性然而,心脏成纤维细胞和CM/CF串扰在心肌细胞发生中的作用,
仍然未知。我们假设致瘤DCM基因激活成纤维细胞并诱导心律失常,
直接或间接地通过它们与心肌细胞的相互作用。hiPSC-CM和心脏成纤维细胞
(hiPSC-CF)将从来自我们的登记研究(Aim 1)的60名患者和具有以下特征的基因组编辑的模型生成:
致突变基因(LMNA,FLNC,DSP)和20名年龄/性别/种族匹配的健康人
个体我们将利用工程化心脏组织支架(EHT)来阐明CFs的活化机制
和心律失常,比较iPSC衍生模型中改变的信号通路与受损心脏中的信号通路。
队列(目标2),并重新拯救表型。
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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Luisa Mestroni其他文献
Luisa Mestroni的其他文献
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{{ truncateString('Luisa Mestroni', 18)}}的其他基金
Cardiomyocyte phenotype and mechanotransduction in Filamin C gene variants causing arrhythmogenic cardiomyopathy
导致致心律失常性心肌病的Filamin C基因变异的心肌细胞表型和机械转导
- 批准号:
10542755 - 财政年份:2020
- 资助金额:
$ 72.73万 - 项目类别:
Cardiomyocyte phenotype and mechanotransduction in Filamin C gene variants causing arrhythmogenic cardiomyopathy
导致致心律失常性心肌病的Filamin C基因变异的心肌细胞表型和机械转导
- 批准号:
9885476 - 财政年份:2020
- 资助金额:
$ 72.73万 - 项目类别:
Cardiomyocyte phenotype and mechanotransduction in Filamin C gene variants causing arrhythmogenic cardiomyopathy
导致致心律失常性心肌病的Filamin C基因变异的心肌细胞表型和机械转导
- 批准号:
10333325 - 财政年份:2020
- 资助金额:
$ 72.73万 - 项目类别:
Molecular Epidemiology of Dilated Cardiomyopath
扩张型心肌病的分子流行病学
- 批准号:
6849697 - 财政年份:2002
- 资助金额:
$ 72.73万 - 项目类别:
Molecular Epidemiology of Dilated Cardiomyopath
扩张型心肌病的分子流行病学
- 批准号:
6696272 - 财政年份:2002
- 资助金额:
$ 72.73万 - 项目类别:
Molecular Epidemiology of Dilated Cardiomyopath
扩张型心肌病的分子流行病学
- 批准号:
6421322 - 财政年份:2002
- 资助金额:
$ 72.73万 - 项目类别:
Molecular Epidemiology of Dilated Cardiomyopath
扩张型心肌病的分子流行病学
- 批准号:
6620728 - 财政年份:2002
- 资助金额:
$ 72.73万 - 项目类别:
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