Intercalated disc-nuclear lamina coupling as a molecular substrate for arrhythmogenic cardiomyopathy
闰盘-核层耦合作为致心律失常性心肌病的分子底物
基本信息
- 批准号:10713689
- 负责人:
- 金额:$ 69.92万
- 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:2023-08-01 至 2027-07-31
- 项目状态:未结题
- 来源:
- 关键词:AccelerationAdhesionsArchitectureArrhythmiaArrhythmogenic Right Ventricular DysplasiaAttentionCardiacCardiac MyocytesCardiomyopathiesCell CommunicationCell DeathCell NucleusCell membraneCell surfaceCell-Matrix JunctionCellsChromatinCodeComplexCouplingCytoskeletonDNA DamageDataDesminDesmosomesDiseaseDisease ProgressionEcosystemFilamentFoundationsFunctional disorderGene ExpressionGenesGenetic DiseasesGenetic EpistasisGenetic TranscriptionGenomeGenomicsHeart ArrestHereditary DiseaseHomeostasisHumanImageInduced MutationIntercalated discIntermediate FilamentsKnowledgeLamin Type ALaminsLifeLinkMechanicsMediatingMethodsMicroscopyMicrotubulesModernizationMolecularMorbidity - disease rateMusMuscle CellsMutant Strains MiceMutationMyocardialMyocardial dysfunctionMyocardiumNuclearNuclear EnvelopeNuclear LaminaNuclear StructureOnset of illnessOrganellesPathogenesisPathologicPathway interactionsPatientsPhysiologyProteinsProteomeProteomicsPublishingReportingResearchRoleSamplingSignal TransductionStructureSurfaceTP53 geneTestingTissuesTranslatingVariantVentricularVentricular ArrhythmiaWorkarrhythmogenic cardiomyopathydesmoplakindisease phenotypedruggable targetenv Gene Productsexperimental studygene repressionmechanical loadmolecular imagingmortalitymouse modelnovel therapeutic interventionpharmacologicplakophilin 2preventresponsescaffoldsingle moleculetranscriptional reprogrammingtranscriptomicstransmission process
项目摘要
Plakophilin-2 (PKP2) is classically defined as a protein of the desmosome, an intercellular adhesion structure
residing in the cardiac intercalated disc (ID). Mutations in PKP2 associate with most cases of gene-positive
arrhythmogenic right ventricular cardiomyopathy (ARVC), a disease characterized by high propensity to life-
threatening arrhythmias and myocardial structural damage, often of right ventricular predominance. Much
attention has been given to the loss of cell-cell attachment at the ID as a disease mechanism. Yet, it is becoming
evident that PKP2 mutations also lead to an array of poorly understood cardiomyocyte (CM)-intrinsic
disturbances. Desmin intermediate filaments are anchored to the desmosome in a PKP2-dependent manner,
supporting CM structural integrity and facilitating communication from the cell surface to the nucleus. Our prior
work in mouse models and human patient samples found PKP2 mutation disrupts CM nuclear envelope (NE)
integrity and leads to DNA damage. Based on published reports and our preliminary data, we hypothesize that
PKP2 deficiency, or disease relevant PKP2 mutations, disrupt the structural, functional and molecular integrity
of the cardiomyocyte nuclear envelope, leading to genomic reorganization, the DNA damage response, and
altered transcription. The following aims will investigate how PKP2 deficiency disrupts the nucleus to accelerate
ARVC disease progression.
Aim 1: Define the impact of PKP2 deficiency on the cardiomyocyte nuclear lamina protein interactome.
We hypothesize that PKP2 deficiency alters the proteome of the cardiomyocyte NE, and that this disruption is
an early trigger for the disease phenotype. We will interrogate changes in the molecular ecosystem of the
cardiomyocyte NE after loss of PKP2 expression using proteomics and single molecule imaging.
Aim 2: Define the impact of PKP2 deficiency on cardiomyocyte genomic organization.
We hypothesize that loss of NE integrity in PKP2 deficient CMs disrupts genomic organization at Lamin
Associated Domains and causes transcriptional remodeling. We will determine how structural damage is
transmitted from the cell membrane to the genome, focusing on changes that occur in the vicinity of the NE
through advanced imaging, genomic and transcriptomic approaches.
Aim 3: Investigate strategies to reduce DDR and delay cardiomyopathy in PKP2 deficient mice.
We hypothesize data that PKP2 mutation induces P53-dependent DNA damage response (DDR), which may
exacerbate ARVC disease progression. Genetic epistasis experiments and pharmacological approaches will
investigate how the P53-dependent DDR contributes to PKP2-dependent cardiomyopathy.
Defining pathological changes to nuclear architecture that precede overt myocardial structural remodeling
will reveal exciting opportunities for new therapeutic strategies aimed at slowing ARVC disease progression by
restoring nuclear envelope homeostasis or preventing the DNA damage response.
Plakophilin-2(PKP 2)被经典地定义为桥粒蛋白,桥粒是细胞间粘附结构
存在于心脏闰盘(ID)中。PKP 2的突变与大多数基因阳性的病例有关。
致瘤性右心室心肌病(ARVC)是一种以高生命倾向为特征的疾病,
威胁性心律失常和心肌结构损伤,通常以右心室为主。多
已经注意到ID处细胞-细胞附着的丧失是一种疾病机制。然而,它正在成为
很明显,PKP 2突变也导致了一系列尚不清楚的心肌细胞(CM)-内源性
干扰.结蛋白中间丝以PKP 2依赖的方式锚定在桥粒上,
支持CM结构完整性并促进从细胞表面到细胞核的通讯。我们事先
在小鼠模型和人类患者样本中的工作发现PKP 2突变破坏CM核包膜(NE)
完整性,并导致DNA损伤。根据已发表的报告和我们的初步数据,我们假设,
PKP 2缺陷或疾病相关的PKP 2突变破坏了结构、功能和分子的完整性,
心肌细胞核膜,导致基因组重组,DNA损伤反应,
改变转录。以下目的将研究PKP 2缺陷如何破坏细胞核,
ARVC疾病进展。
目的1:明确PKP 2缺陷对心肌细胞核纤层蛋白相互作用组的影响。
我们假设PKP 2缺陷改变了心肌细胞NE的蛋白质组,并且这种破坏是心肌细胞NE蛋白质组的一个重要因素。
疾病表型的早期触发因素。我们将询问在分子生态系统的变化,
使用蛋白质组学和单分子成像,研究PKP 2表达丧失后心肌细胞NE的变化。
目的2:明确PKP 2缺陷对心肌细胞基因组结构的影响。
我们假设PKP 2缺陷型CM中NE完整性的丧失破坏了核纤层蛋白的基因组组织,
相关的结构域和原因转录重塑。我们将确定结构性损伤
从细胞膜传递到基因组,集中在NE附近发生的变化
通过先进的成像、基因组和转录组学方法。
目的3:研究降低PKP 2缺陷小鼠DDR和延迟心肌病的策略。
我们假设PKP 2突变诱导P53依赖的DNA损伤反应(DDR),这可能
加剧ARVC疾病进展。遗传上位性实验和药理学方法将
研究P53依赖性DDR如何导致PKP 2依赖性心肌病。
明确心肌结构重构前核结构的病理变化
将揭示旨在减缓ARVC疾病进展的新治疗策略的令人兴奋的机会,
恢复核膜稳态或防止DNA损伤反应。
项目成果
期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
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Eric M Small其他文献
Eric M Small的其他文献
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{{ truncateString('Eric M Small', 18)}}的其他基金
Mechanisms of epicardium-directed coronary vessel patterning
心外膜定向冠状血管模式的机制
- 批准号:
10686088 - 财政年份:2022
- 资助金额:
$ 69.92万 - 项目类别:
Coordination of inflammatory signaling and cardiac fibrosis by small proline rich proteins
富含脯氨酸的小蛋白协调炎症信号传导和心脏纤维化
- 批准号:
10305604 - 财政年份:2018
- 资助金额:
$ 69.92万 - 项目类别:
Coordination of inflammatory signaling and cardiac fibrosis by small proline rich proteins
富含脯氨酸的小蛋白协调炎症信号传导和心脏纤维化
- 批准号:
10063897 - 财政年份:2018
- 资助金额:
$ 69.92万 - 项目类别:
Regulation of epicardial cell differentiation during development and disease
发育和疾病过程中心外膜细胞分化的调节
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8786102 - 财政年份:2013
- 资助金额:
$ 69.92万 - 项目类别:
Regulation of epicardial cell differentiation during development and disease
发育和疾病过程中心外膜细胞分化的调节
- 批准号:
8975800 - 财政年份:2013
- 资助金额:
$ 69.92万 - 项目类别:
Regulation of epicardial cell differentiation during development and disease
发育和疾病过程中心外膜细胞分化的调节
- 批准号:
8611390 - 财政年份:2013
- 资助金额:
$ 69.92万 - 项目类别:
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