GSK-3β Localizes to the Myofilament and Modifies its Function in Ischemic Cardiomyopathy

GSK-3β 定位于肌丝并改变其在缺血性心肌病中的功能

基本信息

  • 批准号:
    9287330
  • 负责人:
  • 金额:
    $ 37.11万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2017
  • 资助国家:
    美国
  • 起止时间:
    2017-04-01 至 2022-03-31
  • 项目状态:
    已结题

项目摘要

PROJECT SUMMARY Mortality from myocardial infarction is decreasing; however, survivors are at high risk of developing ischemic cardiomyopathy (ICM). Understanding the mechanisms involved in that transition may help develop methods to prevent it. Ischemic damage produces a form of dyssynchronous contraction that cannot be treated with conventional therapies (Cardiac Resynchronization Therapy, CRT). However, the Principal Investigator previously discovered a critical molecular mechanism of CRT: it reactivates glycogen synthase kinase 3β (GSK-3β) and thus restores myofilament function. This proposal will leverage the molecular mechanism discovered in CRT in a patient population that cannot respond to it, ICM patients. Preliminary data reveals that human and mouse ICM samples exhibit myofilament calcium desensitization, and exogenous treatment with GSK-3β restores calcium sensitivity, suggesting the functional defect is linked to deactivation of GSK-3β. Further, new preliminary data has identified an independently regulated pool of GSK-3β localized to the myofilament that decreases significantly in human ICM, which correlates with the decrease in calcium sensitivity. Importantly, additional preliminary data suggest the localization of GSK-3β to the myofilament is mediated by phosphorylation of GSK-3β at tyrosine 216. This could allow targeted modulation of the myofilament pool of GSK-3β as a therapeutic strategy to improve myofilament function. Thus, based on these new preliminary data, this proposal addresses the central hypothesis that ischemia de-activates a myofilament pool of GSK-3β via altering tyrosine 216 (Y216) phosphorylation, decreasing phosphorylation of its myofilament targets and depressing myofilament function. There are three specific aims. Aim 1 will address the hypothesis that ICM decreases myofilament function in a GSK-3β dependent manner. Genetic mouse models that alter GSK-3β activity will be subjected to surgical induction of myocardial infarction to generate ICM and then myofilament function and GSK-3β activity will assayed. Human tissue from ICM patients will be studied similarly. Aim 2 will address the the hypothesis that phosphorylation at Y216 on GSK-3β modulates its binding to the myofilament and ICM decreases the amount and activity of GSK- 3β at the myofilament. Mutant forms of GSK-3β where the Y216 site is unphosphorylatable or mimic constitutive phosphorylation will be expressed in cardiac myocytes to determine where and how GSK-3β binds to the myofilament. Myofilament function will also be assessed to determine whether these mutant forms of GSK-3β can restore function in the GSK-3β knock-out mouse. The last aim will address the hypothesis that GSK-3β can normalize the myofilament phospho-proteome in ICM patients and ICM mouse tissue using state of the art mass spectrometry approaches. The long-term objective of this project is to identify the mechanisms by which GSK-3β affects myofilament function in the ICM heart, with the goal of discovering a therapeutic approach to prevent the transition to ischemic cardiomyopathy after a myocardial infarction.
项目概要 心肌梗塞死亡率正在下降;然而,幸存者患缺血性心脏病的风险很高 心肌病(ICM)。了解这种转变所涉及的机制可能有助于开发方法 防止它。缺血性损伤会产生一种无法用药物治疗的不同步收缩 常规疗法(心脏再同步疗法,CRT)。然而,首席研究员 先前发现了 CRT 的一个关键分子机制:它重新激活糖原合成酶激酶 3β (GSK-3β) 从而恢复肌丝功能。该提案将利用分子机制 在 CRT 中发现无法对其做出反应的患者群体,即 ICM 患者。初步数据显示 人类和小鼠 ICM 样本表现出肌丝钙脱敏作用,以及外源性治疗 GSK-3β 恢复钙敏感性,表明功能缺陷与 GSK-3β 失活有关。 此外,新的初步数据已经确定了一个独立调节的 GSK-3β 池,该池位于 肌丝在人类 ICM 中显着减少,这与钙的减少相关 敏感性。重要的是,额外的初步数据表明 GSK-3β 在肌丝中的定位是 由 GSK-3β 在酪氨酸 216 处的磷酸化介导。这可以允许靶向调节 GSK-3β 肌丝池作为改善肌丝功能的治疗策略。因此,基于这些 新的初步数据,该提案提出了一个中心假设,即缺血使 GSK-3β 肌丝池通过改变酪氨酸 216 (Y216) 磷酸化,减少 其肌丝靶标磷酸化并抑制肌丝功能。有三个 具体目标。目标 1 将解决 ICM 降低 GSK-3β 中肌丝功能的假设 依赖方式。改变 GSK-3β 活性的基因小鼠模型将接受手术诱导 心肌梗塞产生ICM,然后检测肌丝功能和GSK-3β活性。人类 来自 ICM 患者的组织也将进行类似的研究。目标 2 将解决以下假设:磷酸化位于 GSK-3β 上的 Y216 调节其与肌丝的结合,ICM 降低 GSK-3β 的数量和活性 3β位于肌丝上。 GSK-3β 的突变形式,其中 Y216 位点不可磷酸化或类似 组成型磷酸化将在心肌细胞中表达,以确定 GSK-3β 的结合位置和方式 到肌丝。还将评估肌丝功能以确定这些突变形式是否 GSK-3β可以恢复GSK-3β敲除小鼠的功能。最后一个目标将解决以下假设: GSK-3β可以使用状态使ICM患者和ICM小鼠组织中的肌丝磷酸化蛋白质组正常化 最先进的质谱方法。该项目的长期目标是确定机制 GSK-3β 通过影响 ICM 心脏中的肌丝功能,目标是发现一种治疗方法 预防心肌梗死后转变为缺血性心肌病的方法。

项目成果

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JONATHAN A KIRK其他文献

JONATHAN A KIRK的其他文献

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{{ truncateString('JONATHAN A KIRK', 18)}}的其他基金

Cardiac Sarcomere Protein Quality Control in Health and Disease
健康和疾病中的心脏肌节蛋白质量控制
  • 批准号:
    10621229
  • 财政年份:
    2017
  • 资助金额:
    $ 37.11万
  • 项目类别:
Cardiac Sarcomere Protein Quality Control in Health and Disease
健康和疾病中的心脏肌节蛋白质量控制
  • 批准号:
    10445976
  • 财政年份:
    2017
  • 资助金额:
    $ 37.11万
  • 项目类别:
GSK-3β Localizes to the Myofilament and Modifies its Function in Ischemic Cardiomyopathy
GSK-3β 定位于肌丝并改变其在缺血性心肌病中的功能
  • 批准号:
    9903442
  • 财政年份:
    2017
  • 资助金额:
    $ 37.11万
  • 项目类别:

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