Pathophysiological Regulation of Atrial Myocyte Excitation-Contraction Coupling and Calcium Signaling
心房肌细胞兴奋-收缩耦合和钙信号传导的病理生理调节
基本信息
- 批准号:9924276
- 负责人:
- 金额:$ 38.75万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-07-01 至 2022-04-30
- 项目状态:已结题
- 来源:
- 关键词:ATP phosphohydrolaseAction PotentialsAffectAnimal ExperimentsAnimalsAtrial FunctionBiochemistryBuffersCalciumCalcium SignalingCalcium ionCalsequestrinCardiacCardiac OutputCellsClosure by clampComplementComputer ModelsConfocal MicroscopyCongestive Heart FailureCouplingDiffuseDiffusionEchocardiographyEndoplasmic ReticulumEnsureEventFire - disastersGene TransferGoalsHeartHeart AtriumHeart DiseasesHeart failureHumanITPR1 geneImmunohistochemistryIndividualInositolInvestigationMeasurementMembraneMicrofilamentsMitochondriaModelingMolecularMuscle CellsOrganOryctolagus cuniculusPathologicPeripheralPlayPropertyProteinsPumpReactionReceptor ActivationRegulationResolutionRiskRoleRyanodine Receptor Calcium Release ChannelSarcoplasmic ReticulumSignal TransductionSiteSpecific qualifier valueSpeedStructureSystemTechniquesTestingTherapeuticTimeTransgenic AnimalsVentricularVentricular RemodelingWorkcardiogenesiscytosolic receptordensityexperimental studyhemodynamicsin vivointerestnovelparallel computerphotolysisreceptorspatiotemporaltripolyphosphateuptakevoltage
项目摘要
PROJECT SUMMARY/ABSTRACT
In atrial myocytes excitation-contraction coupling (ECC) and Ca release from the sarcoplasmic reticulum (SR)
have unique features that result from the lack or the irregular organization of the transverse tubule membrane
system. Atrial myocytes have two types of SR, junctional (j-SR) and non-junctional (nj-SR). Ca release from j-
SR is controlled by Ca entry through voltage-gated L-type Ca channels whereas release from nj-SR occurs by
subsequent propagating Ca-induced Ca release (CICR). In atrial ECC a fundamental question has remained
unanswered: The cardiac ryanodine receptor (RyR) SR Ca release channel has an inherently low cytosolic Ca-
sensitivity resulting in a conundrum how CICR from the nj-SR can even be activated. This investigation aims to
establish a novel comprehensive model of atrial ECC. In heart failure (HF) the heart undergoes structural and
functional changes (cardiac remodeling) that are aimed towards maintaining an adequate cardiac output. We
will investigate how at different stages during the development of HF, remodeling of the atria leads to profound
changes in atrial Ca signaling, ECC and inotropy that contribute to maintaining cardiac output.
Specific aim 1. Determine the unique properties of Ca release in atrial myocytes that ensure robust
CICR. We will test a novel hypothesis of a 'fire-diffuse-uptake-fire' (FDUF) paradigm for atrial Ca release and
ECC. By this mechanism the coordinated action of RyR regulation by cytosolic and luminal Ca (tandem RyR
activation) at the level of individual SR Ca release units as well as the entire SR network, Ca uptake by
sarco/endoplasmic reticulum Ca ATPase and intra-SR Ca diffusion assure robust and efficient CICR.
Specific aim 2: Determine how atrial remodeling of ECC and Ca release during the progression of HF
optimizes cardiac output. We will test the hypothesis that at different stages of HF, stage-specific atrial
remodeling determines cardiac output by altering molecular mechanisms that regulate atrial SR Ca release,
ECC and contractility. The proposed studies will involve molecular, cellular, intact organ and in-vivo whole
animal experiments.
We will use a multitude of experimental techniques: high resolution [Ca]i, [Ca]mito and [Ca]SR confocal
microscopy, cell shortening measurements, whole-cell voltage and current clamp techniques, single RyR
channel recordings, subcellular photolysis of caged compounds, adenoviral gene-transfer,
immunohistochemistry and biochemistry techniques. Experimental work is paralleled by computational
modeling of Ca release and ECC. A central role plays a rabbit chronic HF model that recapitulates the
progression of HF in humans. Rabbit experiments will be complemented with studies on transgenic animals
with specific alterations in expression levels of Ca handling proteins crucial to CICR and ECC. Cellular studies
will be paralleled with intact heart hemodynamic studies and in-vivo echocardiographic studies in animals
during progression of HF.
项目概要/摘要
心房肌细胞兴奋-收缩耦合 (ECC) 和肌浆网 (SR) 中的 Ca 释放
由于横管膜缺乏或组织不规则而具有独特的特征
系统。心房肌细胞有两种类型的 SR:交界型 (j-SR) 和非交界型 (nj-SR)。 Ca 从 j 中释放
SR 受 Ca 通过电压门控 L 型 Ca 通道的进入控制,而 nj-SR 的释放则通过
随后传播 Ca 诱导的 Ca 释放 (CICR)。在心房 ECC 中,仍然存在一个基本问题
未解答:心脏兰尼碱受体 (RyR) SR Ca 释放通道具有固有的低胞质 Ca-
敏感性导致了如何激活 nj-SR 的 CICR 的难题。这项调查旨在
建立一种新颖的心房ECC综合模型。在心力衰竭 (HF) 中,心脏会经历结构性和
旨在维持足够的心输出量的功能变化(心脏重塑)。我们
将研究心力衰竭发展的不同阶段,心房重塑如何导致深远的影响
心房 Ca 信号传导、ECC 和正性肌力的变化有助于维持心输出量。
具体目标 1. 确定心房肌细胞 Ca 释放的独特特性,确保其稳健
CICR。我们将测试心房 Ca 释放的“火-扩散-吸收-火”(FDUF) 范式的新假设
ECC。通过这种机制,细胞质和管腔 Ca 的 RyR 调节协调作用(串联 RyR
激活)在单个 SR Ca 释放单元以及整个 SR 网络水平上,Ca 吸收
肌浆/内质网 Ca ATP 酶和 SR 内 Ca 扩散确保稳健且高效的 CICR。
具体目标 2:确定心力衰竭进展过程中 ECC 心房重塑和 Ca 释放的情况
优化心输出量。我们将检验以下假设:在 HF 的不同阶段,特定阶段的心房
重塑通过改变调节心房 SR Ca 释放的分子机制来决定心输出量,
ECC 和收缩性。拟议的研究将涉及分子、细胞、完整器官和体内整体
动物实验。
我们将使用多种实验技术:高分辨率 [Ca]i、[Ca]mito 和 [Ca]SR 共焦
显微镜、细胞缩短测量、全细胞电压和电流钳技术、单 RyR
通道记录、笼中化合物的亚细胞光解、腺病毒基因转移、
免疫组织化学和生物化学技术。实验工作与计算并行
Ca 释放和 ECC 建模。兔慢性心力衰竭模型发挥着核心作用,该模型概括了
人类心力衰竭的进展。转基因动物研究将补充兔子实验
对 CICR 和 ECC 至关重要的 Ca 处理蛋白表达水平的特定改变。细胞研究
将与完整心脏血流动力学研究和动物体内超声心动图研究同时进行
心力衰竭进展期间。
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Effect of carvedilol on atrial excitation-contraction coupling, Ca2+ release, and arrhythmogenicity.
卡维地洛对心房兴奋-收缩耦合、Ca2 释放和致心律失常的影响。
- DOI:
- 发表时间:2020
- 期刊:
- 影响因子:0
- 作者:Martinez;Blatter, L A
- 通讯作者:Blatter, L A
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{{ truncateString('LOTHAR A BLATTER', 18)}}的其他基金
IP3 receptor, NOX2 and calcium signaling domains in atrial physiology and pathophysiology
心房生理学和病理生理学中的 IP3 受体、NOX2 和钙信号传导域
- 批准号:
10443403 - 财政年份:2022
- 资助金额:
$ 38.75万 - 项目类别:
Atrial Excitation-Contraction Coupling, Calcium Signaling and Electro-Mechanical Alternans
心房兴奋-收缩耦合、钙信号传导和机电交替
- 批准号:
10667610 - 财政年份:2022
- 资助金额:
$ 38.75万 - 项目类别:
IP3 receptor, NOX2 and calcium signaling domains in atrial physiology and pathophysiology
心房生理学和病理生理学中的 IP3 受体、NOX2 和钙信号传导域
- 批准号:
10597225 - 财政年份:2022
- 资助金额:
$ 38.75万 - 项目类别:
Pathophysiological Regulation of Atrial Alternans and Atrial Fibrillation
心房交替和心房颤动的病理生理调节
- 批准号:
9907864 - 财政年份:2017
- 资助金额:
$ 38.75万 - 项目类别:
MItochondrial Dysfunction in Cardiac Hypertrophy and Failure
心脏肥大和衰竭中的线粒体功能障碍
- 批准号:
8319979 - 财政年份:2010
- 资助金额:
$ 38.75万 - 项目类别:
MItochondrial Dysfunction in Cardiac Hypertrophy and Failure
心脏肥大和衰竭中的线粒体功能障碍
- 批准号:
8244422 - 财政年份:2010
- 资助金额:
$ 38.75万 - 项目类别:
MItochondrial Dysfunction in Cardiac Hypertrophy and Failure
心脏肥大和衰竭中的线粒体功能障碍
- 批准号:
8451323 - 财政年份:2010
- 资助金额:
$ 38.75万 - 项目类别:
MItochondrial Dysfunction in Cardiac Hypertrophy and Failure
心脏肥大和衰竭中的线粒体功能障碍
- 批准号:
7847834 - 财政年份:2010
- 资助金额:
$ 38.75万 - 项目类别:
MItochondrial Dysfunction in Cardiac Hypertrophy and Failure
心脏肥大和衰竭中的线粒体功能障碍
- 批准号:
8064744 - 财政年份:2010
- 资助金额:
$ 38.75万 - 项目类别:
Ca and InsP3 Receptor Signaling in Cardiac Myocytes
心肌细胞中的 Ca 和 InsP3 受体信号传导
- 批准号:
8207381 - 财政年份:2006
- 资助金额:
$ 38.75万 - 项目类别:
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