CARDIAC NA-CA EXCHANGER: HYPERTROPHIC REGULATION

心脏 NA-CA 交换器:肥厚调节

基本信息

  • 批准号:
    6808221
  • 负责人:
  • 金额:
    $ 16.08万
  • 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

The etiologies of late hypertrophy and heart failure are extremely complex but altered cellular calcium regulation appears to be a final common cause in both arrhythmogenesis and contractile dysfunction. The SR Ca2+-ATPase (SERCA) and sarcolemmal Na+-Ca2+ exchanger (NCX1) are two major transporters responsible for reducing [Ca2+]i to a low resting level during relaxation. SERCA expression and activity are decreased in hypertrophy and failure and we and others have shown that expression and activity in NCX1 is increased in this situation. Recent reports have demonstrated that upregulation of the exchanger appears to be a critical link between contractile dysfunction and arrhythmogenesis. Additional studies have documented the cardio-protective effect resulting from inhibition of calcium influx via NCX1 in ischemia/reperfusion, digitalis toxicity and atrial fibrillation-induced shortening of atrial refractiveness. So far these results are solely based on acute studies and do not address long-term treatment. We discovered that inhibition of NCX1 calcium influx pathway (reverse mode) either by KB-R7943 or by lowering [Ca2+]o, resulted in the activation of signaling factors that leads to specific upregulation of the exchanger gene. This novel and exciting finding should have a profound impact on potential long-term treatment and places regulation of exchanger activity in a whole new light. The exchanger, whose activity is acutely sensitive to [Ca2+]o, [Ca2+]i, [Na+]i, and membrane potential (Em), may also act as a cellular rheostat that plays a role in the modulation of specific signal transduction pathways. Our hypothesis is that alteration of exchanger activity can directly activate signal transduction pathways resulting in changes in exchanger gene expression. This will be tested through the following aims: 1) Determine that the KBR induced activation of p38 and upregulation of NCX1 is directly mediated by the exchanger. 2) Determine whether changes in exchanger activity transduce the activation of signaling pathways by direct interaction or via changes in [Ca2+]i. 3) Identify factors interacting directly with the exchanger that mediate the activation of p38. 4) Identify the downstream factors in the signaling pathway mediating p38 activation. This work will allow us to better understand the role that exchanger activity plays in failure and provide a framework for therapeutic development.
晚期肥厚和心力衰竭的病因极其复杂,但细胞钙调节的改变似乎是血管生成和收缩功能障碍的最终共同原因。肌浆网Ca ~(2+)-ATP酶(SERCA)和肌膜Na ~+-Ca ~(2+)交换器(NCX 1)是两种主要的肌浆网Ca ~(2+)-ATP酶转运体,在肌松过程中负责将[Ca ~(2+)]i降低到较低的静息水平。SERCA表达和活性在肥大和衰竭中降低,并且我们和其他人已经表明在这种情况下NCX 1的表达和活性增加。最近的报告表明,上调的交换似乎是一个关键的联系之间的收缩功能障碍和血管生成。另外的研究已经证明了在缺血/再灌注中通过NCX 1抑制钙内流、洋地黄毒性和心房颤动诱导的心房收缩缩短引起的心脏保护作用。到目前为止,这些结果仅基于急性研究,并不涉及长期治疗。我们发现,通过KB-R7943或通过降低[Ca 2 +]o抑制NCX 1钙内流途径(反向模式),导致信号传导激活 导致交换基因特异性上调的因素。这一新颖而令人兴奋的发现应该对潜在的长期治疗产生深远的影响,并将交换剂活性的调节置于全新的视角。该交换器的活性对[Ca 2 +]o、[Ca 2 +]i、[Na+]i和膜电位(Em)非常敏感,也可以作为细胞变阻器,在特定信号转导途径的调节中发挥作用。我们的假设是,交换活性的改变可以直接激活信号转导途径,导致交换基因表达的变化。这将通过以下目的进行测试:1)确定KBR诱导的p38活化和NCX 1上调直接由交换剂介导。2)确定交换器活性的变化是否通过直接相互作用或通过[Ca 2 +]i的变化抑制信号通路的激活。3)确定直接与介导p38激活的交换器相互作用的因素。4)识别介导p38激活的信号通路中的下游因子。这项工作将使 我们更好地了解交换活性在失败中的作用,并为治疗开发提供框架。

项目成果

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Donald R. Menick其他文献

Two Groups Control Light-Induced Schiff Base Deprotonation and the Proton Affinity of Asp<sup>85</sup> in the Arg<sup>82</sup>His Mutant of Bacteriorhodopsin
  • DOI:
    10.1016/s0006-3495(99)77108-0
  • 发表时间:
    1999-11-01
  • 期刊:
  • 影响因子:
  • 作者:
    Eleonora S. Imasheva;Sergei P. Balashov;Thomas G. Ebrey;Ning Chen;Rosalie K. Crouch;Donald R. Menick
  • 通讯作者:
    Donald R. Menick
Role of p38/Akt Signaling Pathway in the Regulation of Sodium/Calcium Exchanger Expression in Adult Cardiomyocytes
  • DOI:
    10.1016/j.cardfail.2010.06.077
  • 发表时间:
    2010-08-01
  • 期刊:
  • 影响因子:
  • 作者:
    Olga Chernysh;Santhosh K. Mani;Donald R. Menick
  • 通讯作者:
    Donald R. Menick
Cloning of Cardiac, Kidney, and Brain Promoters of the Feline <em>ncx1</em> Gene
  • DOI:
    10.1074/jbc.272.17.11510
  • 发表时间:
    1997-04-25
  • 期刊:
  • 影响因子:
  • 作者:
    Kimberly V. Barnes;Guangmao Cheng;Myra M. Dawson;Donald R. Menick
  • 通讯作者:
    Donald R. Menick
Role of Nkx2.5 Acetylation by Histone Deacetylases in Regulating Sodium/Calcium Exchanger Expression in Adult Cardiomyocytes
  • DOI:
    10.1016/j.cardfail.2010.06.140
  • 发表时间:
    2010-08-01
  • 期刊:
  • 影响因子:
  • 作者:
    Mona S. Li;Santhosh K. Mani;Benjamin Addy;Thirumagal Thiagarajan;Christine B. Kern;Donald R. Menick
  • 通讯作者:
    Donald R. Menick

Donald R. Menick的其他文献

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{{ truncateString('Donald R. Menick', 18)}}的其他基金

ShEEP application for Integrated Hypoxia Exposure and Analysis Core
用于集成缺氧暴露和分析核心的 ShEEP 应用
  • 批准号:
    9795680
  • 财政年份:
    2019
  • 资助金额:
    $ 16.08万
  • 项目类别:
Regulatory Role of HDAC in Post-MI Ventricular Remodeling
HDAC 在 MI 后心室重构中的调节作用
  • 批准号:
    9919999
  • 财政年份:
    2014
  • 资助金额:
    $ 16.08万
  • 项目类别:
Regulatory Role of HDAC in Post-MI Ventricular Remodeling
HDAC 在 MI 后心室重构中的调节作用
  • 批准号:
    10265359
  • 财政年份:
    2014
  • 资助金额:
    $ 16.08万
  • 项目类别:
Regulatroy Role of HDAC in Post-MI Ventricular Remodeling
HDAC 在 MI 后心室重构中的调节作用
  • 批准号:
    8818507
  • 财政年份:
    2014
  • 资助金额:
    $ 16.08万
  • 项目类别:
Regulatory Role of HDAC in Post-MI Ventricular Remodeling
HDAC 在 MI 后心室重构中的调节作用
  • 批准号:
    10455524
  • 财政年份:
    2014
  • 资助金额:
    $ 16.08万
  • 项目类别:
Regulatory Role of HDAC in Post-MI Ventricular Remodeling
HDAC 在 MI 后心室重构中的调节作用
  • 批准号:
    10830235
  • 财政年份:
    2014
  • 资助金额:
    $ 16.08万
  • 项目类别:
Regulatroy Role of HDAC in Post-MI Ventricular Remodeling
HDAC 在 MI 后心室重构中的调节作用
  • 批准号:
    8975085
  • 财政年份:
    2014
  • 资助金额:
    $ 16.08万
  • 项目类别:
MAP4 REGULATION OF CARDIAC MICROTUBULE NETWORK DENSITY
MAP4 心脏微管网络密度的调节
  • 批准号:
    8639216
  • 财政年份:
    2010
  • 资助金额:
    $ 16.08万
  • 项目类别:
MAP4 REGULATION OF CARDIAC MICROTUBULE NETWORK DENSITY
MAP4 心脏微管网络密度的调节
  • 批准号:
    8235944
  • 财政年份:
    2010
  • 资助金额:
    $ 16.08万
  • 项目类别:
MAP4 REGULATION OF CARDIAC MICROTUBULE NETWORK DENSITY
MAP4 心脏微管网络密度的调节
  • 批准号:
    8490586
  • 财政年份:
    2010
  • 资助金额:
    $ 16.08万
  • 项目类别:

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Evaluation of Plasma Concentration of the Antiarrhythmic Agent for Treatment of Fetus Tachycardia
治疗胎儿心动过速的抗心律失常药血浆浓度评价
  • 批准号:
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  • 财政年份:
    2011
  • 资助金额:
    $ 16.08万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
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