Molecular Atlas of the Cardiac Intercalated Disc
心脏闰盘分子图谱
基本信息
- 批准号:10348937
- 负责人:
- 金额:$ 99.8万
- 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:2022-01-20 至 2028-12-31
- 项目状态:未结题
- 来源:
- 关键词:Adherens JunctionAdultAreaArrhythmiaAtlasesCalciumCardiacCell membraneCell physiologyCellsCellular StructuresChemical AgentsComplexConnexin 43DesmosomesDevice or Instrument DevelopmentDiagnosisDisease ProgressionElectronsElectrophysiology (science)ElementsGap JunctionsGenomicsGeometryGrantHeartHeart ArrestIntercalated discKnowledgeLeadLifeMapsMedicalMembraneMethodsMicroscopyMitochondriaModernizationMolecularMorbidity - disease rateMuscle CellsMutateOnset of illnessOrganellesPhysiologyPrevention therapyProteomicsRegulationResearchRisk AssessmentRoleSavingsSiteStructureVentricularVentricular ArrhythmiaVisualWorkbasecancer therapydesigngenomic dataheart rhythmmortalitynovelphenotypic dataplakophilin 2protein complex
项目摘要
PROJECT SUMMARY
This grant proposes research on the molecular mechanisms that control the electrical activity of adult cardiac
ventricular myocytes. Our focus is on the cardiac intercalated disc (ID), a region of the cell recognized as key to
excitability and propagation and yet, only partly characterized in terms of its molecular composition, regulation
and function. Our objective is to obtain a map of this structure by integrating proximity and visual proteomics,
genomics, physiomics and molecule-specific physiology. We will study control hearts as well as those deficient
in Plakophilin-2 (PKP2), an ID molecule that when mutated can cause lethal arrhythmias in the young.
The ID was first described as an interdigitation of cell membranes at the site of end-end apposition between
adult ventricular myocytes, hosting three electron-dense structures: gap junctions, desmosomes and adherens
junctions (later redefined as mixed junctions or area composita1). More recent work shows that the ID also hosts
protein complexes fundamental to electrophysiology. In fact, more than 70 years since it was described as an
electron-dense structure, the ID emerges as a node that congregates the molecular machinery involved in all
aspects of electrical activity: excitation, repolarization, propagation and control of Ca2+i.
Despite the known importance of the ID in cell function, there is a wide knowledge gap regarding its molecular
composition and its varied functional roles. Part of this limitation results from the fact that, as opposed to other
membrane-wrapped cell components (e.g., mitochondria), isolation of the ID as a single organelle has not been
possible given its complex geometry, and the fact that it is open to the cell interior without a limiting barrier of its
own. Here, we circumvent these limitations by combining proximity and visual proteomics. The list of interactors
will serve as a platform to query genomics and phenotype data, and to guide molecule-specific studies.
Cardiac arrhythmias are common, debilitating and in many cases, fatal. Progress has been made in the
development of devices and invasive strategies which, as sophisticated and life-saving as they are, can also
cause serious and irreparable damage to the heart. In the context of medical therapy, the field of arrhythmias
has been lagging behind others (e.g., cancer therapy), where a deep understanding of molecular components
and their interdependence have led to the discovery of chemical agents that can slow down or arrest disease
progression. We do not claim that our study can stop arrhythmias. But we do believe that knowledge of the
molecular elements involved in rhythm control can lead to better risk assessment, diagnosis, prevention and
therapy. The ID is a domain that concentrates multiple rhythm-control molecules and as such, a perfect target
for applying proximity-based methods to advance our knowledge on the control of the heart rhythm.
项目总结
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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Mario Delmar其他文献
Mario Delmar的其他文献
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{{ truncateString('Mario Delmar', 18)}}的其他基金
Role of PKP2 in epicardial structure and function
PKP2 在心外膜结构和功能中的作用
- 批准号:
9262386 - 财政年份:2016
- 资助金额:
$ 99.8万 - 项目类别:
Role of Desmosomes in Cardiac Electrical Function
桥粒在心脏电功能中的作用
- 批准号:
8762968 - 财政年份:2013
- 资助金额:
$ 99.8万 - 项目类别:
2013 Cardiac Arrhythmia Mechanisms Gordon Research Conference
2013年心律失常机制戈登研究会议
- 批准号:
8450492 - 财政年份:2013
- 资助金额:
$ 99.8万 - 项目类别:
Role of Desmosomes in Cardiac Electrical Function
桥粒在心脏电功能中的作用
- 批准号:
8209146 - 财政年份:2011
- 资助金额:
$ 99.8万 - 项目类别:
Role of Desmosomes in Cardiac Electrical Function
桥粒在心脏电功能中的作用
- 批准号:
8389874 - 财政年份:2011
- 资助金额:
$ 99.8万 - 项目类别:
Role of Desmosomes in Cardiac Electrical Function
桥粒在心脏电功能中的作用
- 批准号:
8041749 - 财政年份:2011
- 资助金额:
$ 99.8万 - 项目类别:
Role of Desmosomes in Cardiac Electrical Function
桥粒在心脏电功能中的作用
- 批准号:
8586549 - 财政年份:2011
- 资助金额:
$ 99.8万 - 项目类别:
Stem cells and the fibroblast/adipocyte lineage in arrhythmogenic cardiomyopathy
致心律失常性心肌病中的干细胞和成纤维细胞/脂肪细胞谱系
- 批准号:
7825971 - 财政年份:2009
- 资助金额:
$ 99.8万 - 项目类别:
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