Stretch-Dependent Calcium Signaling in Heart
心脏中拉伸依赖性钙信号传导
基本信息
- 批准号:8392242
- 负责人:
- 金额:$ 35.7万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2011
- 资助国家:美国
- 起止时间:2011-01-01 至 2014-11-30
- 项目状态:已结题
- 来源:
- 关键词:AffectBehaviorBirthCalciumCalcium SignalingCardiacCardiac MyocytesCardiomyopathiesCellsCoupledCytoskeletonDependenceDiastoleDiseaseDuchenne muscular dystrophyDystrophinFoundationsFunctional disorderGoalsHeartHeart DiseasesHigh PrevalenceImageInvestigationLeadLengthMediatingMethodsMicrotubulesModelingMusMuscle CellsMuscular DystrophiesPatientsPhysiologicalProcessPropertyResearchRyR2Ryanodine Receptor Calcium Release ChannelRyanodine ReceptorsSarcoplasmic ReticulumScientistSignal TransductionStressStretchingSystoleTechnologyTimeVentricularWild Type MouseWorkabstractingexperienceflash photolysisheart cellheart functionheart rhythmin vivoinnovationmalemdx mousemouse modelnew technologynovelpatch clampresearch studyresponsetool
项目摘要
Abstract
Ca2+ sparks in heart have been shown by the PI to occur under physiological conditions during diastole
and systole. They not only underlie the normal [Ca2+]i transient but have been found to be critically important in
mediating the cellular response to stress and disease, contributing to contractile and arrhythmic dysfunction in
conditions ranging from calcium overload to the cardiomyopathy of muscular dystrophy. Recently, work by the
PI shows that physiologic stretch, such as that experienced by a myocyte during diastolic filling, dramatically
alters Ca2+ spark occurrence transiently in normal cardiac ventricular myocytes. This behavior depends on
microtubules affecting the release mechanisms of the sarcoplasmic reticulum (SR). Despite the importance of
this new discovery one year ago, we have only now developed the additional tools needed to investigate how
dynamic length changes can affect the triggering of Ca2+ sparks under diverse conditions. Using these new
tools, we observe (in preliminary investigations) that stretch-dependent changes in Ca2+ sparks are even larger
than previously observed and appear to arise from a transient increase in the the sensitivity of ryanodine
receptors (RyR2s). Additional preliminary work shows that, surprisingly, this transient increase in Ca2+ sparks
underlies the activation of arrhythmogenic Ca2+ waves at a very low rate in heart cells from control mice, but at
a much higher rate in myocytes from mdx mice, the murine model of Duchenne muscular dystrophy, or from
control mice with excessive calcium in the SR. The tools developed by the PI and his colleagues will enable
an innovative state-of-the-art investigation into how cardiac Ca2+ signaling is modulated by physiological
stretch. The proposed work seeks to investigate stretch-dependent Ca2+ sparks and Ca2+ waves in 1. control
ventricular myocytes; 2. ventricular myocytes in which RyR2 properties have been altered; 3. ventricular
myocytes when microtubules are modulated; 4. ventricular myocytes from dystrophin null (mdx) mice. The
planned research should reveal for the first time the importance of stretch in normal and pathological Ca2+
signaling of cardiac ventricular myocytes. The work will therefore provide not only fundamental new
information on normal cellular behavior but also on mechanisms of arrhythmogenesis. Furthermore it will lay
the foundation for novel therapies for diverse heart diseases including Duchenne muscular dystrophy.
摘要
PI显示心脏在舒张期的生理状态下会产生钙离子火花
还有收缩。它们不仅是正常的[Ca~(2+)]i瞬变的基础,而且被发现在
介导细胞对应激和疾病的反应,导致心脏收缩和心律失常
从钙超载到肌营养不良的心肌病。最近,由
PI显示,生理性拉伸,如心肌细胞在舒张期充盈时所经历的拉伸,显著地
短暂地改变正常心肌细胞中钙离子火花的发生。此行为取决于
影响肌浆网(SR)释放机制的微管。尽管重要的是
一年前的这一新发现,我们现在才开发出研究如何
在不同的条件下,长度的动态变化会影响钙火花的触发。使用这些新功能
工具,我们观察到(在初步调查中)钙离子火花的伸展依赖变化甚至更大
比以前观察到的更多,似乎是由于兰诺定敏感性的一过性增加引起的
受体(RyR2)。更多的初步研究表明,令人惊讶的是,这种短暂的钙离子增加会引发
在对照组小鼠的心肌细胞中,引起心律失常的钙波以非常低的频率激活,但在
来自MDX小鼠、Duchenne肌营养不良症小鼠模型的心肌细胞的比率要高得多,或者来自
对照组小鼠在SR中钙含量过高。PI和他的同事开发的工具将使
生理性调控心肌细胞内钙信号的最新研究
伸展一下。这项拟议的工作旨在研究1.对照中的拉伸依赖的钙火花和钙波
室肌细胞;2.RyR2特性改变的室肌细胞;3.室肌细胞
微管被调节时的心肌细胞;4.来自dystrophin缺失(MDX)小鼠的心室肌细胞。这个
计划中的研究将首次揭示拉伸在正常和病理性钙离子中的重要性
心肌细胞的信号传导。因此,这项工作不仅将提供根本性的新的
关于正常细胞行为的信息,也关于心律失常发生机制的信息。此外,它还将铺设
为包括杜氏肌营养不良症在内的各种心脏病的新疗法奠定了基础。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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William Jonathan Lederer其他文献
William Jonathan Lederer的其他文献
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{{ truncateString('William Jonathan Lederer', 18)}}的其他基金
Chemo-mechanical signaling in atrial myocytes
心房肌细胞中的化学机械信号传导
- 批准号:
10323655 - 财政年份:2019
- 资助金额:
$ 35.7万 - 项目类别:
Chemo-mechanical signaling in atrial myocytes
心房肌细胞中的化学机械信号传导
- 批准号:
10064006 - 财政年份:2019
- 资助金额:
$ 35.7万 - 项目类别:
Decreased Cholinergic Tone and Mitochondrial Dysfunction in Heart
心脏胆碱能张力降低和线粒体功能障碍
- 批准号:
8327739 - 财政年份:2011
- 资助金额:
$ 35.7万 - 项目类别:
Decreased Cholinergic Tone and Mitochondrial Dysfunction in Heart
心脏胆碱能张力降低和线粒体功能障碍
- 批准号:
8585942 - 财政年份:2011
- 资助金额:
$ 35.7万 - 项目类别:
Decreased Cholinergic Tone and Mitochondrial Dysfunction in Heart
心脏胆碱能张力降低和线粒体功能障碍
- 批准号:
8019904 - 财政年份:2011
- 资助金额:
$ 35.7万 - 项目类别:
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