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

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.
项目概要 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对心脏进行建模,以确定结构的促心律失常作用 和功能异质性并阐明钙 (Ca2+) 波的分子和离子机制,延迟 后除极 (DAD)、室性早搏 (PVC) 以及心室颤动 (VF)。一个 关键成果将是为抗心律失常药物开发、基因疗法和 新的治疗策略。该项目建立在我们最近的发现 1) 异质细胞间耦合的基础上 促进组织尺度上触发的心律失常; 2)异质兰尼碱受体(RyR)分布 在亚细胞尺度上促进致心律失常的 Ca2+ 火花和波。这里提出的工作旨在 弥合组织尺度心律失常机制和亚细胞尺度之间的知识差距 利用多尺度计算模型和最先进的实验的心律失常机制 测量心脏详细异质性的方法。目标#1 是在 RyR 属性之间建立联系 和亚细胞 Ca2+ 动力学。为此,我们将扩展这项研究并研究心力衰竭 (HF) 细胞,这 应该更加异质。我们将测量正常和 HF 细胞中的 RyR 分布并构建 生理和病理模型来检验我们的假设,即异质 RyR 分布促进 Ca2+ 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团簇大小和RyR在裂隙空间的空间排列影响Ca2+火花; 2)RyR如何集群 细胞内的分布促进致心律失常的 Ca2+ 波。 RyR 门控,以及 Ca2+ 火花和波,是 还受到翻译后修饰(PTM)的影响。目标 #2 是检验 PTM 进一步的假设 增加与结构 RyR 异质性相互作用的异质 Ca2+ 瞬变。 SERCA 再摄取是 Ca2+ 循环中的另一个关键角色。增加 SERCA 泵活性会增加 SR Ca2+ 负荷,从而促进 波传播。同时,增加 SERCA 泵活性可减少胞质 Ca2+ 瞬变,从而 抑制波的传播。在目标 #3 中,我们测试了增加 SERCA 泵功能具有以下效果的假设: 对致心律失常 Ca2+ 波倾向的双相效应。当 Ca2+ 波出现时,它们会使细胞去极化 膜并可能导致组织中的触发活动。如果细胞耦合良好,就会立即去极化 被周围细胞吸收。然而,当细胞间耦合减少时,去极化就无法实现。 被周围细胞吸收,聚氯乙烯更容易发生。然而,与此同时,减少了细胞间的 耦合使波的传播更加困难。因此,我们假设存在一个最优的细胞间 PVC 形成的耦合(目标#4)。所提出的工作将建立一个新的范式,一些不规则的 Ca2+ 当心力衰竭和其他疾病的心脏异质性增加时,火花可能导致整个心律失常 病理状况。

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

Training Program in Pharmacology
药理学培训计划
  • 批准号:
    10656570
  • 财政年份:
    2022
  • 资助金额:
    $ 39.25万
  • 项目类别:
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:
Project 2 (Bers)
项目2(Bers)
  • 批准号:
    10677715
  • 财政年份:
    2019
  • 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:
Project 2 (Bers)
项目2(Bers)
  • 批准号:
    10006341
  • 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:
Project 2 (Bers)
项目2(Bers)
  • 批准号:
    10249148
  • 财政年份:
    2019
  • 资助金额:
    $ 39.25万
  • 项目类别:
Project 2 (Bers)
项目2(Bers)
  • 批准号:
    10471339
  • 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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