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
- 来源:
- 关键词:ATP phosphohydrolaseAddressAdenovirusesAffectAnimal ModelBindingBiological AssayCalciumCardiac MyocytesCell Culture TechniquesCellsCo-ImmunoprecipitationsDataDefectDepressed moodDeteriorationDilated CardiomyopathyEchocardiographyExhibitsGYS1 geneGeneticGoalsHeartHeart failureHeterogeneityHumanHybridsImmunofluorescence ImmunologicInfarctionIschemiaKnockout MiceLabelLaboratoriesLinkMass Spectrum AnalysisMeasuresMediatingMethodsMicrofilamentsMolecularMotionMusMuscle CellsMutateMyocardial InfarctionOperative Surgical ProceduresPacemakersPatientsPhosphorylationPhosphorylation SitePhosphotransferasesPrincipal InvestigatorProtein KinaseProteinsProteomeRecombinant ProteinsRoleSamplingSiteSkinStructureSurvivorsTestingTherapeuticTherapeutic InterventionTissuesTyrosineVentricularYeastsbasecardiac resynchronization therapyconventional therapydesensitizationexperimental studyfunctional restorationglycogen synthase kinase 3 betaheart cellhigh riskhuman tissueimprovedin vivoischemic cardiomyopathymortalitymouse modelmutantpatient populationpreventrepairedtherapeutic target
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
期刊论文数量(0)
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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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