Mechanisms of E-C Coupling in Atrial Cells

心房细胞电-电耦合机制

基本信息

  • 批准号:
    7124340
  • 负责人:
  • 金额:
    $ 36.25万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2003
  • 资助国家:
    美国
  • 起止时间:
    2003-08-01 至 2008-07-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Normal excitation-contraction (EC) coupling in mammalian cardiac cells requires the coordinated release of calcium (Ca2+) from the sarcoplasmic reticulum (SR). In mammalian ventricular cells, the extensive transverse-tubular (t-tubular) system conducts electrical depolarization rapidly to the cell interior that triggers a near synchronous release of C2+ from the SR and subsequent activation of the myofibrils throughout the cell. Because atrial cells lack an extensive t-tubular network, the coordination of SR Ca2+-release and contraction in atrial cells must depend on an entirely different cellular process. The aim of the proposed research is to answer the question, "What is (are) the cellular mechanism(s) responsible for the transduction of membrane depolarization to subsequent contraction in cardiac atrial cells?" The overall hypotheses of this proposed project are (1) that the mechanism of coupling Ca2+-entry through L-type Ca2+ channels and Ca2+-release from the SR at the peripheral couplings of atrial cells is the same as that which occurs at the t-tubular-junctional SR region in ventricular cells, and (2) that because of the absence of a well-organized t-tubular system in atrial cells, the normal physiological mechanisms of SR Ca2+-release away from the peripheral couplings are entirely different. Specific aim 1 tests the hypothesis that the relationship between Ca2+-entry via L-type Ca2+ channels and Ca2+-release from the SR at the peripheral couplings in atrial cells is identical to that in the t-tubular-junctional SR region of ventricular cells. Specific aim 2 tests the hypothesis that both propagated and non-propagated Ca2+-release occur in atrial cells and that the type of Ca2+-release is determined by SR Ca2+-load, ryanodine receptor (RyR) Ca2+-sensitivity, and the magnitude and duration of the Ca2+-entry through L-type Ca2+ channels. Specific aim 3 tests the hypothesis that the magnitude and velocity of contraction depends on the type of Ca2+-release (non-propagating or propagating) and the "diffusional" size of the cell. We hypothesize that an increase in the cell circumference triggers a switch between non-propagating and propagating Ca2+-release, thereby providing a means for maintaining the speed and magnitude of contraction despite differences in cell size. Specifically, we test (1) that non-propagating Ca2+-release can elicit rapid and large contractions in atrial cells with small circumference. (2) Propagating Ca2+-waves are needed to cause rapid and large contractions in atrial cells with a large circumference. (3) The transverse axial tubular system (TATS), by reducing diffusional distances, allows non-propagating Ca2+-release to cause rapid and large contractions in large atrial cells. This proposal uniquely combines mathematical modeling, cellular electrophysiology and Ca2+ imaging and will provide a quantitative understanding of Ca2+ homeostasis in cardiac atrial cells.
描述(由申请人提供):哺乳动物心脏细胞中的正常兴奋-收缩(EC)偶联需要从肌浆网(SR)中协调释放钙(Ca 2+)。在哺乳动物心室细胞中,广泛的横管(t-管)系统将电去极化快速传导至细胞内部,其触发从SR的C2+的近同步释放和随后的整个细胞的肌原纤维的激活。由于心房细胞缺乏广泛的t-管网络,因此心房细胞中SR Ca 2+释放和收缩的协调必须依赖于完全不同的细胞过程。这项研究的目的是回答这样一个问题:“在心脏心房细胞中,膜去极化到随后收缩的转导是什么细胞机制?“该项目的总体假设是:(1)在心房细胞的外周耦合处,通过L型Ca 2+通道的Ca 2+进入和从SR释放Ca 2+的耦合机制与心室细胞中t管连接SR区域发生的机制相同,以及(2)由于心房细胞中缺乏组织良好的t管系统,SR Ca 2 +-释放远离外周偶联的正常生理机制是完全不同的。具体目标1测试的假设,通过L型Ca 2+通道和Ca 2+释放之间的关系,从SR在心房细胞的外周耦合是相同的,在t-管连接的SR区域的心室细胞。具体目标2检验了以下假设:心房细胞中发生增殖性和非增殖性Ca 2+释放,并且Ca 2+释放的类型由SR Ca 2+负荷、兰尼碱受体(RyR)Ca 2+敏感性以及通过L型Ca 2+通道进入Ca 2+的幅度和持续时间决定。具体目标3测试收缩的幅度和速度取决于Ca 2+释放的类型(非传播或传播)和细胞的“扩散”大小的假设。我们假设细胞周长的增加触发了非传播和传播Ca 2+释放之间的转换,从而提供了一种尽管细胞大小不同但仍能保持收缩速度和幅度的方法。具体而言,我们测试(1)非传播性Ca 2+释放可以引起小周长心房细胞的快速和大的收缩。(2)心房肌细胞的快速大幅度收缩需要Ca 2+波的增强。(3)横轴管系统(TATS),通过减少扩散距离,允许非传播的Ca 2+释放,引起快速和大的收缩在大心房细胞。该建议独特地结合了数学建模,细胞电生理学和Ca 2+成像,并将提供定量的了解Ca 2+稳态心脏心房细胞。

项目成果

期刊论文数量(5)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Cardiomyopathy-causing deletion K210 in cardiac troponin T alters phosphorylation propensity of sarcomeric proteins.
  • DOI:
    10.1016/j.yjmcc.2010.01.005
  • 发表时间:
    2010-05
  • 期刊:
  • 影响因子:
    5
  • 作者:
    Sfichi-Duke L;Garcia-Cazarin ML;Sumandea CA;Sievert GA;Balke CW;Zhan DY;Morimoto S;Sumandea MP
  • 通讯作者:
    Sumandea MP
Funding opportunities for investigators in the early stages of career development.
为研究人员职业发展早期阶段提供资助机会。
  • DOI:
    10.1161/circulationaha.107.752691
  • 发表时间:
    2009
  • 期刊:
  • 影响因子:
    37.8
  • 作者:
    Sumandea,CAmelia;Balke,CWilliam
  • 通讯作者:
    Balke,CWilliam
Cardiac troponin T, a sarcomeric AKAP, tethers protein kinase A at the myofilaments.
心肌肌钙蛋白 T 是一种肌节 AKAP,将蛋白激酶 A 束缚在肌丝上。
  • DOI:
    10.1074/jbc.m110.148684
  • 发表时间:
    2011
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Sumandea,CAmelia;Garcia-Cazarin,MaryL;Bozio,CatherineH;Sievert,GailA;Balke,CWilliam;Sumandea,MariusP
  • 通讯作者:
    Sumandea,MariusP
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C. William Balke其他文献

The Ca2+ synapse redo: a matter of location, location, location.
Ca2 突触重做:位置、位置、位置的问题。
  • DOI:
  • 发表时间:
    2002
  • 期刊:
  • 影响因子:
    20.1
  • 作者:
    L. Izu;C. William Balke
  • 通讯作者:
    C. William Balke
Calcium signalling in cardiac muscle cells.
心肌细胞中的钙信号传导。
  • DOI:
    10.1002/9780470514696.ch9
  • 发表时间:
    1995
  • 期刊:
  • 影响因子:
    0
  • 作者:
    W. Wier;José Ramón López;P. S. Shacklock;C. William Balke
  • 通讯作者:
    C. William Balke
Transcription Profiles of Failing and Non-Failing Hearts after Two-Cycle RNA Amplification from Biopsy-Sized Samples
  • DOI:
    10.1016/j.cardfail.2006.06.144
  • 发表时间:
    2006-08-01
  • 期刊:
  • 影响因子:
  • 作者:
    Brian R. Barrows;Agnes Azimzadeh;Stacey L. McCulle;Gloria Vives-Rodriguez;Stacey L. McCulle;C. William Balke;Richard N. Pierson;Stephen S. Gottlieb;Frances L. Johnson;Meredith Bond
  • 通讯作者:
    Meredith Bond
"Oh, the places you'll go": transformation of the nation's biomedical research enterprise in the 21st century.
《哦,你要去的地方》:21世纪国家生物医学研究事业的转型。
  • DOI:
  • 发表时间:
    2010
  • 期刊:
  • 影响因子:
    1.7
  • 作者:
    C. William Balke;Gloria H. Umberger;C. Mattacola
  • 通讯作者:
    C. Mattacola
ARM EXERCISE ELECTROCARDIOGRAPHIC STRESS TESTING VERSUS REGADENASON MYOCARDIAL PERFUSION IMAGING AND EXERCISE TREADMILL TESTING FOR CLINICAL OUTCOME PREDICTION
  • DOI:
    10.1016/s0735-1097(20)30832-9
  • 发表时间:
    2020-03-24
  • 期刊:
  • 影响因子:
  • 作者:
    Douglas Kyrouac;Anandita Kulkarni;Divya Kapoor;Jiafu Ou;C. William Balke;Hong Xian;Medhat Osman;Wade Martin
  • 通讯作者:
    Wade Martin

C. William Balke的其他文献

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{{ truncateString('C. William Balke', 18)}}的其他基金

Identification of Novel Cellular/Molecular Mechanisms and Arrhythmia Targets in Heart Failure
心力衰竭的新型细胞/分子机制和心律失常目标的鉴定
  • 批准号:
    9891155
  • 财政年份:
    2020
  • 资助金额:
    $ 36.25万
  • 项目类别:
Identification of Novel Cellular/Molecular Mechanisms and Arrhythmia Targets in Heart Failure
心力衰竭的新型细胞/分子机制和心律失常目标的鉴定
  • 批准号:
    10618857
  • 财政年份:
    2020
  • 资助金额:
    $ 36.25万
  • 项目类别:
Identification of Novel Cellular/Molecular Mechanisms and Arrhythmia Targets in Heart Failure
心力衰竭的新型细胞/分子机制和心律失常目标的鉴定
  • 批准号:
    10454757
  • 财政年份:
    2020
  • 资助金额:
    $ 36.25万
  • 项目类别:
CA Permeable Na Channels & Cardiac Cell Excitation
CA 渗透性 Na 通道
  • 批准号:
    6795076
  • 财政年份:
    2003
  • 资助金额:
    $ 36.25万
  • 项目类别:
Training Grant in Cardiac and Vascular Cell Biology
心脏和血管细胞生物学培训补助金
  • 批准号:
    6593658
  • 财政年份:
    2003
  • 资助金额:
    $ 36.25万
  • 项目类别:
CA Permeable Na Channels & Cardiac Cell Excitation
CA 渗透性 Na 通道
  • 批准号:
    6683087
  • 财政年份:
    2003
  • 资助金额:
    $ 36.25万
  • 项目类别:
Mechanisms of E-C Coupling in Atrial Cells
心房细胞电-电耦合机制
  • 批准号:
    6560698
  • 财政年份:
    2003
  • 资助金额:
    $ 36.25万
  • 项目类别:
CA Permeable Na Channels & Cardiac Cell Excitation
CA 渗透性 Na 通道
  • 批准号:
    6942358
  • 财政年份:
    2003
  • 资助金额:
    $ 36.25万
  • 项目类别:
Mechanisms of E-C Coupling in Atrial Cells
心房细胞电-电耦合机制
  • 批准号:
    6783421
  • 财政年份:
    2003
  • 资助金额:
    $ 36.25万
  • 项目类别:
CA Permeable Na Channels & Cardiac Cell Excitation
CA 渗透性 Na 通道
  • 批准号:
    7123785
  • 财政年份:
    2003
  • 资助金额:
    $ 36.25万
  • 项目类别:

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  • 批准号:
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  • 财政年份:
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