Detyrosinated microtubules in cardiomyocyte mechanics

心肌细胞力学中的去酪氨酸微管

基本信息

  • 批准号:
    9914295
  • 负责人:
  • 金额:
    $ 40.25万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2016
  • 资助国家:
    美国
  • 起止时间:
    2016-07-01 至 2021-08-31
  • 项目状态:
    已结题

项目摘要

Project Summary: “Detyrosinated microtubules in cardiomyocyte mechanics” The microtubule cytoskeleton performs a number of cellular functions including cargo transport and structural support. In certain forms of heart disease there is an extensive proliferation and post-translational modification of the microtubule network that correlates with declining contractility. It has previously been suggested that the increased density of microtubules may provide an intrinsic mechanical resistance to cardiac contraction, and therefore that targeting microtubules may restore contractility in heart disease. However, a detailed mechanistic understanding of how microtubules provide resistance is lacking, and this line of research has stalled. The PI and colleagues have made two important advances to move this field forward. First, we have developed imaging and labeling tools to observe and characterize microtubule behavior in beating heart cells. We observe that microtubules function like springs in the beating heart, a challenge to the conventional view. These spring like microtubules provide a mechanical resistance to heart cell contraction and stretch. Second, we have identified a novel element that appears to regulate the mechanical properties of the cytoskeleton. In new published (Kerr et al. Nature Communications, 2015) and preliminary evidence we show that detyrosination, a post-translational modification of tubulin, regulates the compression-resistance of the cytoskeleton and alters the spring-like behavior of microtubules. Importantly, reducing detyrosination decreases mechanical resistance and increases myocyte contractility, suggesting a potential therapeutic benefit in heart disease. In this proposal we will thus test the hypothesis that detyrosination increases cytoskeletal compression resistance, and that specifically reducing detyrosination can improve contractility in heart failure. We have 3 major goals of our proposal: 1) to determine if increasing detyrosination is sufficient to impair myocyte mechanics; 2) to determine the molecular mechanism by which detyrosination influences cytoskeletal mechanics; 3) to determine if increased detyrosination impairs myocyte function in human heart disease. Our team of cardiomyocyte physiologists, cytoskeletal biologists, and a cardiac physician scientist are ideally suited to achieving these goals. The successful completion of this work will reveal mechanistic insight into how detyrosination alters cytoskeletal mechanics, a finding with broad relevance to cell biology and with specific translational implications for human cardiac disease.
项目总结: 《心肌细胞力学中的去旋化微管》 微管细胞骨架执行许多细胞功能,包括货物运输和结构 支持。在某些形式的心脏病中,有广泛的增殖和翻译后修饰 与收缩能力下降相关的微管网络。此前曾有人建议, 微管密度的增加可能对心脏收缩提供内在的机械抵抗,以及 因此,靶向微管可能会恢复心脏病的收缩能力。然而,一份详细的 对微管如何提供抵抗力的机制缺乏了解,而这一系列研究已经 停滞不前。 PI和他的同事们在推动这一领域向前发展方面取得了两项重要进展。首先,我们有 开发了成像和标记工具来观察和表征心脏跳动细胞中的微管行为。 我们观察到,微管的功能就像跳动的心脏中的弹簧,这是对传统观点的挑战。 这些像弹簧一样的微管为心脏细胞的收缩和拉伸提供了机械阻力。第二, 我们已经确定了一种新的元件,它似乎调节细胞骨架的机械性能。在……里面 新出版(Kerr等人自然通讯,2015)和初步证据表明 去酪氨酸化是微管蛋白的翻译后修饰,调节细胞的抗压能力 细胞骨架并改变微管的弹力式行为。重要的是,减少腐败 减少机械阻力并增加心肌细胞的收缩能力,这表明一种潜在的治疗方法 有益于心脏病。 因此,在这个提案中,我们将检验去酪氨酸化会增加细胞骨架压缩这一假设。 这种特殊的减少酪氨酸酶排泄可以改善心力衰竭患者的收缩能力。我们有3个 我们建议的主要目标:1)确定增加的酪氨酸酶降解是否足以损害心肌细胞 2)确定酪氨酸酶影响细胞骨架的分子机制 力学;3)确定变性增加是否会损害人类心脏病的心肌细胞功能。我们的 由心肌细胞生理学家、细胞骨架生物学家和一名心脏内科科学家组成的团队非常适合 为实现这些目标干杯。这项工作的成功完成将揭示如何从机械上洞察 酪氨酸化改变细胞骨架力学,这一发现与细胞生物学和特异性 人类心脏病的翻译含义。

项目成果

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Benjamin Lears Prosser其他文献

Benjamin Lears Prosser的其他文献

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{{ truncateString('Benjamin Lears Prosser', 18)}}的其他基金

MicroRNA site-blocking oligonucleotides as a novel therapy for neurodevelopmental disorders
MicroRNA 位点阻断寡核苷酸作为神经发育障碍的新型疗法
  • 批准号:
    10302244
  • 财政年份:
    2021
  • 资助金额:
    $ 40.25万
  • 项目类别:
Detyrosinated microtubules in cardiomyocyte mechanics
心肌细胞力学中的去酪氨酸微管
  • 批准号:
    10296019
  • 财政年份:
    2016
  • 资助金额:
    $ 40.25万
  • 项目类别:
Detyrosinated microtubules in cardiomyocyte mechanics
心肌细胞力学中的去酪氨酸微管
  • 批准号:
    10678948
  • 财政年份:
    2016
  • 资助金额:
    $ 40.25万
  • 项目类别:
Detyrosinated microtubules in cardiomyocyte mechanics
心肌细胞力学中的去酪氨酸微管
  • 批准号:
    10469698
  • 财政年份:
    2016
  • 资助金额:
    $ 40.25万
  • 项目类别:
Detyrosinated microtubules in cardiomyocyte mechanics
心肌细胞力学中的去酪氨酸微管
  • 批准号:
    9157065
  • 财政年份:
    2016
  • 资助金额:
    $ 40.25万
  • 项目类别:
Detyrosinated microtubules in cardiomyocyte mechanics
心肌细胞力学中的去酪氨酸微管
  • 批准号:
    9279248
  • 财政年份:
    2016
  • 资助金额:
    $ 40.25万
  • 项目类别:
Stretch-dependent X-ROS signaling: implications for cardiomyopathy
拉伸依赖性 X-ROS 信号传导:对心肌病的影响
  • 批准号:
    8803862
  • 财政年份:
    2014
  • 资助金额:
    $ 40.25万
  • 项目类别:
Stretch-dependent X-ROS signaling: implications for cardiomyopathy
拉伸依赖性 X-ROS 信号传导:对心肌病的影响
  • 批准号:
    8849495
  • 财政年份:
    2014
  • 资助金额:
    $ 40.25万
  • 项目类别:
Stretch-dependent X-ROS signaling: implications for cardiomyopathy
拉伸依赖性 X-ROS 信号传导:对心肌病的影响
  • 批准号:
    8354544
  • 财政年份:
    2012
  • 资助金额:
    $ 40.25万
  • 项目类别:
Stretch-dependent X-ROS signaling: implications for cardiomyopathy
拉伸依赖性 X-ROS 信号传导:对心肌病的影响
  • 批准号:
    8532974
  • 财政年份:
    2012
  • 资助金额:
    $ 40.25万
  • 项目类别:

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