Regulation of cellular calcium by cardiac sodium-calcium exchange
通过心脏钠钙交换调节细胞钙
基本信息
- 批准号:9766112
- 负责人:
- 金额:$ 66.76万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-04-15 至 2023-02-28
- 项目状态:已结题
- 来源:
- 关键词:AblationAcidosisAcuteAddressAdrenergic beta-AgonistsAdultAffectAffinityArrhythmiaCRISPR/Cas technologyCa(2+)-Transporting ATPaseCalciumCardiacCardiac MyocytesCardiac pacemakerCell DeathCell membraneCellsChronicCouplingDataDependenceDevelopmentDigoxinDiseaseEFRACElectrophysiology (science)ExcisionFunctional disorderGene ExpressionGenerationsGoalsGrantHeartHeart AtriumHeart BlockHeart DiseasesHeart failureHomeostasisHospitalizationImaging TechniquesKnock-in MouseKnock-outKnockout MiceLaboratoriesMusMuscle CellsMyocardial InfarctionMyocardial dysfunctionMyocardiumNodalOpticsPacemakersPatch-Clamp TechniquesPhysiologicalPhysiologyPreventionProteinsProteomicsPumpRegulationRestRoleSick Sinus SyndromeSinoatrial NodeSodiumSodium-Calcium ExchangerSpeedStructureSystoleTamoxifenTemperatureTestingTherapeuticTimeTissuesVentricularWorkatrioventricular nodecell growth regulationcell injuryconfocal imagingexperimental studyextracellularheart cellheart functionimplantationimprovedinnovationinsightmouse modelnext generationnovelprogramsrelease of sequestered calcium ion into cytoplasmsensortissue preparationtranscriptome sequencingvoltage
项目摘要
The purpose of this MPI proposal between the Goldhaber and Ottolia laboratories is to improve our
mechanistic understanding of how sodium-calcium exchange (NCX), the dominant calcium (Ca) efflux
mechanism in cardiac cells, functions to regulate cellular Ca, which in turn controls contractility and pacemaker
activity. Our labs have been studying the exchanger for more than two decades, despite a number of
challenges: 1) there is no proven specific blocker of NCX that can be administered extracellularly; 2) NCX
current is sometimes difficult to interpret because the transporter is influenced not only by voltage, but also by
temperature, pH and the intracellular and extracellular concentrations of Na and Ca; 3) intracellular Ca is not
only transported by the exchanger, but also serves a regulatory function that can influence transport activity. In
addition to our longstanding expertise isolating and studying NCX, for this proposal we have generated new
highly innovative NCX mouse models: a tamoxifen-inducible cardiac knockout of NCX, which allows us to
investigate how Ca regulation adapts over time to the acute removal of NCX in the adult mouse; a unique pH-
insensitive NCX knockin mouse to investigate the physiological impact of NCX pH regulation; and the first
ventricular-specific plasma membrane Ca pump 1 (PMCA1) KO mouse to determine the relative contribution of
NCX and PMCA to Ca homeostasis and EC coupling. Our three specific aims are to study: 1. Atrial-Specific
NCX KO–Effects on Nodal Rhythm and Atrial EC Coupling; 2. Acute and Chronic Adaptations of
Ventricular EC Coupling and Ca regulation to Genetically Altered Levels of NCX; 3. NCX pH
dependence – implications for EC coupling and arrhythmia. These aims will test the hypotheses that NCX
is an essential component of atrioventricular node (AVN) conduction and impulse generation, that acute
ablation of NCX in adult mice activates a Ca regulatory and EC coupling adaptation program that is distinct
from chronic adaptation, that PMCA1 is a critical alternative to NCX as a Ca efflux mechanism, and that pH
sensitivity of NCX is critical for maintaining Ca regulation under conditions of low pH. Our approach is to use
our existing and new innovative mouse models, along with state-of-the-art single cell and tissue
electrophysiology combined with high speed subcellular Ca imaging techniques, high-quality proteomics and
next generation RNA sequencing, to determine how NCX contributes to cardiac function through regulation of
Ca. When completed, these studies will improve our mechanistic understanding of the role of NCX and related
Ca handling proteins in cellular Ca regulation, EC coupling, and cardiac pacemaker (SAN and AVN) function.
Such information is critical to develop effective and safe approaches to improving contractility and cellular
pacemaker function in cardiac diseases such as heart failure with reduced ejection fraction, and high degree
heart block from AVN disease.
Goldhaber和Ottolia实验室之间的MPI提案的目的是改善我们的
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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Joshua I Goldhaber其他文献
Joshua I Goldhaber的其他文献
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{{ truncateString('Joshua I Goldhaber', 18)}}的其他基金
Cardiac Myocyte Protein Partners in Heart Function
心肌细胞蛋白在心脏功能中的伙伴
- 批准号:
10502152 - 财政年份:2022
- 资助金额:
$ 66.76万 - 项目类别:
Cardiac Myocyte Protein Partners in Heart Function
心肌细胞蛋白在心脏功能中的伙伴
- 批准号:
10667626 - 财政年份:2022
- 资助金额:
$ 66.76万 - 项目类别:
Regulation of cellular calcium by cardiac sodium-calcium exchange
通过心脏钠钙交换调节细胞钙
- 批准号:
9906764 - 财政年份:2019
- 资助金额:
$ 66.76万 - 项目类别:
Regulation of cellular calcium by cardiac sodium-calcium exchange
通过心脏钠钙交换调节细胞钙
- 批准号:
10376807 - 财政年份:2019
- 资助金额:
$ 66.76万 - 项目类别:
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