Desmosomes in cardiomyocyte homeostasis and disease
桥粒在心肌细胞稳态和疾病中的作用
基本信息
- 批准号:10606894
- 负责人:
- 金额:$ 81.65万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-12-15 至 2026-11-30
- 项目状态:未结题
- 来源:
- 关键词:ATAC-seqAblationAccelerationAdhesivesAdipose tissueAdultArrhythmiaBiomedical EngineeringCardiacCardiac MyocytesCardiomyopathiesCell NucleusCellsChemicalsComplexDISC componentsDataDesmosomesDevelopmentDiseaseDissectionElementsExperimental ModelsFluorescent in Situ HybridizationFunctional disorderGene ExpressionGene Expression RegulationGenesGeneticGenetic TranscriptionGoalsHeart AbnormalitiesHeart failureHomeostasisHumanIn Situ HybridizationIntercalated discKnowledgeLeadLifeLinkMetabolismMethodsModelingMolecularMusMuscle functionMutationMyocardial ContractionMyocardial dysfunctionMyocardiumN-CadherinPathogenesisPathway interactionsPatientsPeriodicityPhenotypePlasmaProteinsProteomicsRegulatory ElementRelaxationResolutionRoleSarcomeresSignal TransductionTestingVentricular ArrhythmiaWNT Signaling Pathwayarrhythmogenic cardiomyopathycandidate identificationcandidate selectiondefined contributiondesmoplakinfollow-upgain of functiongenetic approachheart rhythmimprovedin vivoinduced pluripotent stem cellinhibitorinnovationinsightloss of functionmosaicmultiple omicsmutantnovelpreservationprotein functionsingle moleculesingle nucleus RNA-sequencingtranscriptometranscriptomics
项目摘要
SUMMARY
Intercalated disks (ICDs) connect the termini of adjacent cardiomyocytes (CMs) physically, electrically, and
chemically. The structural role of ICDs to preserve CM integrity in the face of billions of cycles of forceful con-
traction and relaxation is well appreciated; however, the function of ICDs as essential CM signaling hubs is
only now emerging. Arrhythmogenic cardiomyopathy (ACM) provides a unique window into the function of
ICDs and specifically desmosomes. ACM is a potentially lethal disorder characterized by high arrhythmia bur-
den, loss of contractile myocardium, and replacement by fibro-fatty tissue. Mutations of desmosome genes
(PKP2, DSG2, DSC2, DSP, JUP) occur in approximately half of ACM patients. Despite growing knowledge
about ACM disease pathogenesis, the mechanistic links between desmosome mutations and arrhythmias, my-
ocardial dysfunction, and fibrofatty replacement remain poorly understood.
The overall goal of this proposal is to gain insights into the mechanisms by which desmosome mutations
cause arrhythmia and myocardial dysfunction; Our overarching hypothesis is that desmosomes are inte-
gral for maintaining normal cardiomyocyte homeostasis through both their structural and signaling
activities. ACM mutations disrupt these activities to cause both loss of structural integrity and aberrant
signaling. We will test these hypotheses through four parallel but complementary Specific Aims: (1) We will
examine cell composition and gene regulation of human ACM myocardium, using concurrent single nucleus
RNA-seq and ATAC-seq, and spatial transcriptomics (snMulti-seq) with massively parallel single molecule fluo-
rescent in situ hybridization (MERFISH); (2) We will use mosaic, adult, cardiomyocyte specific inactivation of
Dsp to probe the cell autonomous functions of desmosomes. This model will be studied using snMulti-seq and
MERFISH, followed by interrogation of key predicted regulators using in vivo gain- and loss-of-function ap-
proaches; (3) Using proximity proteomics of ICD component N-cadherin, we identified novel ICD components
and ICD components that are altered by Dsp ablation. We will use in vivo gain- and loss-of-function ap-
proaches to study the function of selected candidates identified by this screen; (4) Define the contributions of
WNT and GSK3 signaling to ACM phenotypes in DSP mutant hiPSC-CMs. Using genetic approaches in bioen-
gineered hiPSC-CMs, we will dissect the involvement of GSK3 and WNT signaling to ACM pathogenesis.
Impact: This proposal will advance our understanding of the function of desmosomes and ICDs in CM
homeostasis and the molecular pathogenesis of ACM. This knowledge will accelerate efforts to develop
targeted ACM therapies.
总结
夹层盘(ICD)将相邻心肌细胞(CM)的末端物理地、电地和生物学地连接在一起。
化学上ICD在面对数十亿次强有力的控制周期时保持CM完整性的结构性作用,
牵引和放松是很好的赞赏;然而,ICD作为重要的CM信号中枢的功能,
现在才刚刚出现。致心律失常性心肌病(ACM)提供了一个独特的窗口,
ICD,特别是桥粒。ACM是一种潜在的致命疾病,其特征是高心律失常,
DEN、收缩性心肌的丧失和被纤维脂肪组织替代。桥粒基因突变
(PKP2、DSG 2、DSC 2、DSP、JUP)在大约一半的ACM患者中发生。尽管知识不断增长
关于ACM疾病的发病机制,桥粒突变和心律失常之间的机制联系,我-
心脏功能障碍和纤维脂肪替代仍然知之甚少。
这项提案的总体目标是深入了解桥粒突变的机制,
导致心律失常和心肌功能障碍;我们的总体假设是桥粒是介导的,
GRAL通过其结构和信号传导维持正常心肌细胞稳态
活动ACM突变破坏了这些活性,导致结构完整性的丧失和异常的蛋白质表达。
发信号。我们将通过四个平行但互补的具体目标来检验这些假设:(1)我们将
用并行单核细胞技术检测人ACM心肌的细胞组成和基因调控
RNA-seq和ATAC-seq,以及空间转录组学(snMulti-seq)与大规模平行单分子荧光检测,
(2)我们将使用嵌合体、成体、心肌细胞特异性失活的
利用Dsp探讨桥粒的细胞自主功能。该模型将使用snMulti-seq进行研究,
MERFISH,然后使用体内获得和丧失功能的ap-1询问关键的预测调节因子。
(3)利用ICD组分N-cadherin的邻近蛋白质组学,我们鉴定了新的ICD组分
以及通过Dsp消融改变的ICD组件。我们将使用体内功能获得和丧失的ap-
研究通过该屏幕识别的所选候选人的功能;(4)定义
DSP突变体hiPSC-CM中WNT和GSK 3信号传导至ACM表型。在生物工程中使用遗传方法-
我们将详细分析GSK 3和WNT信号通路在ACM发病机制中的作用。
影响:该提案将促进我们对CM中桥粒和ICD功能的理解
动态平衡和ACM的分子发病机制。这些知识将加速开发
针对性ACM治疗。
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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{{ truncateString('William Tswenching Pu', 18)}}的其他基金
CMYA5 regulation of cardiac dyad structure and function
CMYA5对心脏二元体结构和功能的调节
- 批准号:
10607816 - 财政年份:2022
- 资助金额:
$ 81.65万 - 项目类别:
Genetic regulation of atrial gene expression in development and disease
发育和疾病中心房基因表达的遗传调控
- 批准号:
10576399 - 财政年份:2021
- 资助金额:
$ 81.65万 - 项目类别:
Genetic regulation of atrial gene expression in development and disease
发育和疾病中心房基因表达的遗传调控
- 批准号:
10355481 - 财政年份:2021
- 资助金额:
$ 81.65万 - 项目类别:
Enabling mammalian in vivo forward genetic screens based on cell morphology
实现基于细胞形态的哺乳动物体内正向遗传筛选
- 批准号:
9754850 - 财政年份:2018
- 资助金额:
$ 81.65万 - 项目类别:
Transcriptional regulation of arteriovenous differentiation
动静脉分化的转录调控
- 批准号:
9751955 - 财政年份:2017
- 资助金额:
$ 81.65万 - 项目类别:
Transcriptional regulation of arteriovenous differentiation
动静脉分化的转录调控
- 批准号:
9376461 - 财政年份:2017
- 资助金额:
$ 81.65万 - 项目类别:
2015 Weinstein Cardiovaascular Development Conference
2015年韦恩斯坦心血管发展大会
- 批准号:
8911591 - 财政年份:2015
- 资助金额:
$ 81.65万 - 项目类别:
YAP1 Regulation of cardiomyocyte proliferation, function, and regeneration
YAP1 对心肌细胞增殖、功能和再生的调节
- 批准号:
8412652 - 财政年份:2013
- 资助金额:
$ 81.65万 - 项目类别:
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