Modelling structural and functional heterogeneity in heart failure reveals arrhythmic impact
心力衰竭的结构和功能异质性建模揭示了心律失常的影响
基本信息
- 批准号:10449125
- 负责人:
- 金额:$ 39.25万
- 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:2019-07-01 至 2024-06-30
- 项目状态:已结题
- 来源:
- 关键词:Action PotentialsAddressAffectAnti-Arrhythmia AgentsArrhythmiaBloodCalciumCardiacCause of DeathCell membraneCellsCoupledCouplingElectrophysiology (science)ExhibitsFeedbackFrequenciesGap JunctionsGoalsHeartHeart failureHeterogeneityHot SpotIndividualIon ChannelIonsKnowledgeLeadLinkMeasuresModelingMolecularMovementMuscle CellsOrganOutcomePathologicPhosphorylationPhysiologicalPost-Translational Protein ProcessingProcessPropertyPumpRegulationRyanodine Receptor Calcium Release ChannelSafetySourceStructural ModelsStructureTechniquesTestingTimeTissuesTravelUnited StatesVariantVentricularVentricular FibrillationVentricular Premature ComplexesWorkbasecalmodulin-dependent protein kinase IIcomplex biological systemsdriving forcedrug developmentexperimental studygene therapyinnovationinsightmathematical analysismathematical modelmulti-scale modelingnovel therapeutic interventionoxidationphospholambanrecruitreuptakesudden cardiac deaththeoriesuptake
项目摘要
PROJECT SUMMARY
The heart is a highly complex biological system. The overall goal of this project is to use multiscale computational
modeling of the heart from the molecular level to the organ level to identify the pro-arrhythmic effects of structural
and functional heterogeneity and elucidate molecular and ionic mechanisms of calcium (Ca2+) waves, delayed
afterdepolarizations (DADs), premature ventricular contractions (PVCs), and thus ventricular fibrillation (VF). A
key outcome will be to provide physiological bases for antiarrhythmic drug development, gene therapies, and
novel therapeutic strategies. The project builds on our recent discoveries 1) heterogeneous cell-to-cell coupling
promotes triggered arrhythmias at the tissue scale; 2) heterogeneous ryanodine receptor (RyR) distribution
promotes arrhythmogenic Ca2+ sparks and waves at the subcellular scale. The work proposed here is aimed
at bridging the knowledge gap between the tissue scale arrhythmia mechanisms and the subcellular scale
arrhythmia mechanisms utilizing multiscale computational modeling and the state-of-the-art experimental
approaches to measure detailed heterogeneity in the heart. Aim #1 is to establish link between RyR properties
and subcellular Ca2+ dynamics. To do this, we will extend this study and investigate heart failure (HF) cells, which
are supposed to be more heterogeneous. We will measure RyR distributions in normal and HF cells and build
the physiological and pathological models to test our hypothesis that heterogeneous RyR distribution promotes
Ca2+ waves, DADs, PVCs, and thus focal arrhythmias. Key questions that we will address in Aim #1 are: 1) how
RyR cluster size and spatial arrangements of RyRs at the cleft space affect Ca2+ sparks; 2) how RyR cluster
distribution in the cell promotes arrhythmogenic Ca2+ waves. RyR gating, and thus Ca2+ sparks and waves, are
also influenced by posttranslational modifications (PTMs). Aim #2 is to test the hypothesis that PTMs further
increase heterogeneous Ca2+ transients interacting with structural RyR heterogeneity. SERCA reuptake is
another key player in the Ca2+ cycling. Increasing SERCA pump activity increases SR Ca2+ load, which promotes
wave propagation. At the same time, increasing SERCA pump activity reduces cytosolic Ca2+ transients, which
suppresses wave propagation. In Aim #3, we test the hypothesis that increasing SERCA-pump function has a
biphasic effect on propensity of arrhythmogenic Ca2+ waves. When Ca2+ waves occur, they depolarize the cell
membrane and can lead to triggered activity in tissue. If cells are well-coupled, depolarization will be immediately
absorbed by surrounding cells. However, when cell-to-cell coupling is reduced, depolarization cannot be
absorbed by surrounding cells and PVCs occur more easily. However, at the same time, reduced cell-to-cell
coupling makes wave propagation more difficult. Therefore, we hypothesize that there is an optimal cell-to-cell
coupling for PVC formation (Aim #4). The proposed work will establish a new paradigm that a few irregular Ca2+
sparks can lead to the whole heart arrhythmias when cardiac heterogeneity is increased in HF and other
pathological conditions.
项目摘要
心脏是一个高度复杂的生物系统。该项目的总体目标是使用多尺度计算
从分子水平到器官水平的心脏建模,以确定结构性的促炎作用。
和功能异质性,并阐明钙(Ca 2+)波的分子和离子机制,延迟
后除极(DAD)、室性早搏(PVC),以及因此的心室颤动(VF)。一
关键成果将是为抗肿瘤药物开发、基因治疗和
新颖的治疗策略。该项目建立在我们最近的发现1)异质细胞间耦合
在组织尺度上促进触发性心律失常; 2)异质性兰尼碱受体(RyR)分布
在亚细胞尺度上促进促细胞增殖的Ca 2+火花和波动。这里提出的工作旨在
在弥合组织规模心律失常机制和亚细胞规模之间的知识差距,
心律失常机制,利用多尺度计算建模和最先进的实验
测量心脏详细异质性的方法。目标#1是建立RyR属性之间的联系
和亚细胞Ca 2+动力学。为了做到这一点,我们将扩大这项研究,并研究心力衰竭(HF)细胞,
应该是更异质的。我们将测量正常和HF细胞中的RyR分布,
生理和病理模型来检验我们的假设,即异质性RyR分布促进
Ca 2+波,DAD,PVC,以及局灶性心律失常。我们将在目标1中解决的关键问题是:1)如何
RyR簇的大小和RyR在裂隙空间的空间排列方式对Ca ~(2+)火花的影响; 2)RyR簇如何在裂隙空间中形成
细胞中的分布促进致心律失常的Ca 2+波。RyR门控,因此Ca 2+火花和波,
也受到翻译后修饰(PTMs)的影响。目的#2是检验PTM进一步
增加与结构RyR异质性相互作用的异质性Ca 2+瞬变。SERCA再摄取是
钙循环的另一个关键因素。增加SERCA泵活性增加SR Ca 2+负荷,这促进
波传播同时,增加SERCA泵活性减少胞质Ca 2+瞬变,
抑制波的传播。在目标3中,我们检验了增加SERCA泵功能具有一定作用的假设
双相效应对促钙波倾向的影响。当Ca 2+波发生时,它们使细胞脱钙,
膜,并可导致组织中的触发活动。如果细胞耦合良好,去极化将立即发生。
被周围的细胞吸收。然而,当细胞与细胞的耦合减少时,去极化就不能发生。
被周围细胞吸收,PVC更容易发生。然而,与此同时,
耦合使得波的传播更加困难。因此,我们假设存在最佳的细胞间
用于PVC形成的偶联(目标#4)。本工作将建立一个新的范式,即少量不规则Ca ~(2+)
当心脏异质性在HF和其他心脏疾病中增加时,火花可导致整个心脏心律失常。
病理条件。
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)
Multi-Scale Computational Modeling of Spatial Calcium Handling From Nanodomain to Whole-Heart: Overview and Perspectives.
- DOI:10.3389/fphys.2022.836622
- 发表时间:2022
- 期刊:
- 影响因子:4
- 作者:Colman MA;Alvarez-Lacalle E;Echebarria B;Sato D;Sutanto H;Heijman J
- 通讯作者:Heijman J
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Donald M Bers其他文献
The Difference of Calmodulin-Ryanodine Receptor Affinity Between N-terminal, Central and C-terminal RyR2-CPVT Knock-in Mice
N端、中央端和C端RyR2-CPVT敲入小鼠钙调蛋白-兰尼定受体亲和力的差异
- DOI:
- 发表时间:
2019 - 期刊:
- 影响因子:0
- 作者:
Hitoshi Uchinoumi;Xiaoqiong Dong;Ivanita Stefanon;Mena Said;Rogerio Faustino;Razvan L Cornea;Univ of Minnesota;Xander H.t. Wehrens; Takeshi Yamamoto;Masafumi Yano;Donald M Bers - 通讯作者:
Donald M Bers
Beyond beta blockers
超越β受体阻滞剂
- DOI:
10.1038/nm0405-379 - 发表时间:
2005-04-01 - 期刊:
- 影响因子:50.000
- 作者:
Donald M Bers - 通讯作者:
Donald M Bers
Donald M Bers的其他文献
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{{ truncateString('Donald M Bers', 18)}}的其他基金
Systems Approach to Understanding Cardiovascular Disease and Arrhythmias - Cell diversity in the cardiovascular system, cell-autonomous and cell-cell signaling
了解心血管疾病和心律失常的系统方法 - 心血管系统中的细胞多样性、细胞自主和细胞间信号传导
- 批准号:
10386681 - 财政年份:2021
- 资助金额:
$ 39.25万 - 项目类别:
Systems Approach to Understanding Cardiac Arrhythmias Mechanisms
了解心律失常机制的系统方法
- 批准号:
9763307 - 财政年份:2019
- 资助金额:
$ 39.25万 - 项目类别:
Modelling structural and functional heterogeneity in heart failure reveals arrhythmic impact
心力衰竭的结构和功能异质性建模揭示了心律失常的影响
- 批准号:
10199780 - 财政年份:2019
- 资助金额:
$ 39.25万 - 项目类别:
CaMKII activation and regulation in adult cardiac myocytes
成人心肌细胞中 CaMKII 的激活和调节
- 批准号:
10687251 - 财政年份:2018
- 资助金额:
$ 39.25万 - 项目类别:
High-Throughput Screens to Discover Novel Inhibitors of Leaky RyR2 for Heart Failure Therapy
高通量筛选发现用于心力衰竭治疗的漏性 RyR2 新型抑制剂
- 批准号:
10064096 - 财政年份:2018
- 资助金额:
$ 39.25万 - 项目类别:
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