The Mitochondrial ATP-Sensitive K+ Channel in Heart

心脏中线粒体 ATP 敏感 K 通道

基本信息

  • 批准号:
    7762806
  • 负责人:
  • 金额:
    $ 36.63万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2002
  • 资助国家:
    美国
  • 起止时间:
    2002-06-01 至 2011-12-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Cardiac ischemia and its sequelae are major causes of mortality. Opening KATP channels exerts a powerful anti-infarct effect, offering the possibilities of a therapeutic target and of insights into the mechanisms of endogenous cardioprotection. The mitochondrial ATP-sensitive K+ channel (mitoKATP) plays a pivotal role in cardioprotection. The long-term goal of this project is to uncover the mechanisms of this action with respect to its role in cell signaling and its role as an end effector of protection. The rationale for our approach is based on the widely accepted conclusion that signaling pathways involving mitoKATP must occur, at least in part, inside the mitochondrion. The specific aims are [1] To determine the topology and localization of kinases within the mitochondrial signaling pathway. [2] To determine how mitoKATP is opened by ischemic preconditioning and how mitoKATP opening is regulated under pathophysiological conditions. [3] To determine the mechanisms by which mitoKATP opening causes the signal to be transmitted to the end effectors of cardioprotection. [4] To determine the downstream targets of mitoKATP opening and mitoKATP-induced signaling by reactive oxygen species (ROS). [5] To determine the biochemistry of the signaling sequence extending from the cytosol to mitoKATP. [6] To determine the molecular identity of mitoKATP. To address these aims, experiments will focus on the perfused heart, isolated mitochondria, fractionation of mitochondrial membranes, and fractionation/purification of membrane proteins. Mechanisms of K+ transport will be studied using light scattering and ion-specific fluorescent probes. The bioenergetics of mitochondrial ROS production will be studied with fluorescent probes. Effects of treatment of the perfused heart will be evaluated in isolated mitochondria using immunodetection and K+ flux measurement techniques. Identification of signaling intermediates will utilize 32P-labeling and functional assays of phosphorylation.
描述(申请人提供): 心脏缺血及其后遗症是死亡的主要原因。打开 KATP 通道可发挥强大的抗梗塞作用,为治疗靶点和深入了解内源性心脏保护机制提供了可能性。线粒体 ATP 敏感 K+ 通道 (mitoKATP) 在心脏保护中发挥着关键作用。该项目的长期目标是揭示这种作用的机制,即其在细胞信号传导中的作用及其作为保护末端效应器的作用。我们的方法的基本原理是基于广泛接受的结论,即涉及 mitoKATP 的信号通路必须至少部分地发生在线粒体内部。具体目标是 [1] 确定线粒体信号通路内激酶的拓扑结构和定位。 [2] 确定缺血预处理如何打开 mitoKATP 以及在病理生理条件下如何调节 mitoKATP 打开。 [3] 确定mitoKATP开放导致信号传递至心脏保护末端效应器的机制。 [4] 确定 mitoKATP 打开的下游靶点和活性氧 (ROS) 诱导的 mitoKATP 信号传导。 [5] 确定从细胞质延伸到 mitoKATP 的信号序列的生物化学。 [6] 确定mitoKATP的分子身份。为了实现这些目标,实验将集中于灌注心脏、分离线粒体、线粒体膜的分级分离以及膜蛋白的分级/纯化。将使用光散射和离子特异性荧光探针来研究 K+ 传输机制。将使用荧光探针研究线粒体 ROS 产生的生物能学。将使用免疫检测和 K+ 通量测量技术在分离的线粒体中评估灌注心脏的治疗效果。信号中间体的鉴定将利用 32P 标记和磷酸化功能测定。

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)
Mitochondrial reactive oxygen species: which ROS signals cardioprotection?
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Keith D Garlid其他文献

Keith D Garlid的其他文献

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{{ truncateString('Keith D Garlid', 18)}}的其他基金

Role of The Mitok ATP Channel in Digitalis Signaling in the Heart
Mitok ATP 通道在心脏洋地黄信号传导中的作用
  • 批准号:
    8250442
  • 财政年份:
    2011
  • 资助金额:
    $ 36.63万
  • 项目类别:
Role of The Mitok ATP Channel in Digitalis Signaling in the Heart
Mitok ATP 通道在心脏洋地黄信号传导中的作用
  • 批准号:
    7664210
  • 财政年份:
    2009
  • 资助金额:
    $ 36.63万
  • 项目类别:
Mitochondrial ATP-Sensitive K+ Channel in Heart
心脏中线粒体 ATP 敏感 K 通道
  • 批准号:
    6685153
  • 财政年份:
    2002
  • 资助金额:
    $ 36.63万
  • 项目类别:
Regulation of Novel Mitochondrial Uncoupling Proteins
新型线粒体解偶联蛋白的调控
  • 批准号:
    6800843
  • 财政年份:
    2002
  • 资助金额:
    $ 36.63万
  • 项目类别:
Mitochondrial ATP-Sensitive K+ Channel in Heart
心脏中线粒体 ATP 敏感 K 通道
  • 批准号:
    6751996
  • 财政年份:
    2002
  • 资助金额:
    $ 36.63万
  • 项目类别:
Mitochondrial ATP-Sensitive K+ Channel in Heart
心脏中线粒体 ATP 敏感 K 通道
  • 批准号:
    6900969
  • 财政年份:
    2002
  • 资助金额:
    $ 36.63万
  • 项目类别:
Regulation of Novel Mitochondrial Uncoupling Proteins
新型线粒体解偶联蛋白的调控
  • 批准号:
    6644177
  • 财政年份:
    2002
  • 资助金额:
    $ 36.63万
  • 项目类别:
The Mitochondrial ATP-Sensitive K+ Channel in Heart
心脏中线粒体 ATP 敏感 K 通道
  • 批准号:
    7341761
  • 财政年份:
    2002
  • 资助金额:
    $ 36.63万
  • 项目类别:
Regulation of Novel Mitochondrial Uncoupling Proteins
新型线粒体解偶联蛋白的调控
  • 批准号:
    6699602
  • 财政年份:
    2002
  • 资助金额:
    $ 36.63万
  • 项目类别:
Mitochondrial ATP-Sensitive K+ Channel in Heart
心脏中线粒体 ATP 敏感 K 通道
  • 批准号:
    6640113
  • 财政年份:
    2002
  • 资助金额:
    $ 36.63万
  • 项目类别:

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