MAP4 REGULATION OF CARDIAC MICROTUBULE NETWORK DENSITY
MAP4 心脏微管网络密度的调节
基本信息
- 批准号:8639216
- 负责人:
- 金额:$ 5.72万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2010
- 资助国家:美国
- 起止时间:2010-04-15 至 2015-03-31
- 项目状态:已结题
- 来源:
- 关键词:AccountingAcidic RegionAdmission activityAdultAffinityAgonistAlzheimer&aposs DiseaseAmericanAmino Acid Repetitive SequencesAmino AcidsAnimal ModelAtrial Heart Septal DefectsBindingBinding SitesBrainCardiacCardiac MyocytesCatalytic DomainCellsCellular MorphologyChimeric ProteinsChronic DiseaseComplexCongestive Heart FailureCytoskeletonDataDefectDiseaseDissociationEmployee StrikesEnzymesExhibitsFailureFamilyFamily FelidaeFiberFunctional disorderG-Protein Signaling PathwayGenesGlycogen Synthase Kinase 3GoalsGrantGrowthGuanosine TriphosphateHealthHeartHeart HypertrophyHeart failureHoloenzymesHospitalsHumanHypertrophyImageIn VitroLeft Ventricular HypertrophyMAP4MediatingMicrofilamentsMicrotubule DepolymerizationMicrotubulesMitogen-Activated Protein KinasesMitosisMitotic spindleModelingMolecularMonomeric GTP-Binding ProteinsMuscleMyocardiumMyofibrilsN-terminalNeuronsOrangesPhenotypePhosphoproteinsPhosphoric Monoester HydrolasesPhosphorylationPhosphorylation SitePhosphotransferasesPhysiologicalPrincipal InvestigatorProlineProline-Rich DomainProtein DephosphorylationProtein FamilyProtein IsoformsProtein Kinase CProtein phosphataseProteinsPulmonary artery structureRegulationResearchRoleSarcoplasmic ReticulumSerineSerine Phosphorylation SiteSignal TransductionSiteStressStructureSystolic heart failureTailTandem Repeat SequencesTissuesTubulinUp-RegulationViscosityWorkagedbasedensitydimergenetic regulatory proteinin vivoinhibitor/antagonistinterestlink proteinmemberoverexpressionp21-activated kinase 1phosphoinositide-dependent kinase 1pressureprogramsreceptor couplingresponsetrafficking
项目摘要
DESCRIPTION (provided by applicant):
We have shown at the levels of isolated cell, isolated tissue and the intact heart in vivo that increased microtubule network density is one cause of contractile dysfunction in high wall stress right or left ventricular hypertrophy. We then showed that increased affinity of microtubule-associated protein 4 [MAP4] for microtubules is the primary determinant of hypertrophy-related microtubule network sta- bilization and densification, and is thereby responsible for both the contractile dysfunction and associ- ated defects in microtubule-based intracellular trafficking that we have also described in this setting. MAP4 phosphorylation status appears to determine MAP4 affinity for microtubules. Therefore, this application intends to characterize the persistent changes in site-specific MAP4 phosphorylation status in an animal model of pathological pressure overload hypertrophy, with a parallel model of physiologi- cal volume overload hypertrophy serving as a control for any effects of growth per se. We will then delineate the regulation of MAP4 phosphorylation by examining relevant kinases and phosphatases. We believe that the successful execution of the proposed research will likely generate important new information to help understand the cellular and molecular mechanisms underlying cardiac hypertro- phy and failure. In addition, while our own end point of interest is the microtubule, the persistent increase in cardiac phosphatase activity and its regulation as shown in our preliminary data is almost certainly of more general importance to established hypertrophy- and failure-related disease mecha- nisms, many of which involve phosphorylation-dependent alterations of structural and regulatory pro- teins of the sarcoplasmic reticulum, the myofibril, and the extra-myofilament cytoskeleton. Thus, this work may serve as an example to help conceptualize the likely mechanistic convergence of a number of heretofore apparently disparate abnormalities of the hypertrophied and failing heart.
描述(由申请人提供):
我们已经在离体细胞、离体组织和完整心脏的水平上表明,微管网络密度增加是高室壁应力右室或左室肥厚收缩功能障碍的原因之一。然后,我们发现微管相关蛋白4 [MAP4]对微管的亲和力增加是肥大相关微管网络稳定和致密化的主要决定因素,从而导致收缩功能障碍和基于微管的细胞内运输的相关缺陷,我们也在此背景下进行了描述。MAP4磷酸化状态似乎决定了MAP4对微管的亲和力。因此,本申请旨在表征病理性压力超负荷肥大动物模型中位点特异性MAP 4磷酸化状态的持续变化,同时将生理性容量超负荷肥大的平行模型用作生长本身任何影响的对照。然后,我们将描绘的MAP 4磷酸化的调节,通过检查相关的激酶和磷酸酶。我们相信,拟议研究的成功执行可能会产生重要的新信息,以帮助理解心脏肥厚和衰竭的细胞和分子机制。此外,虽然我们自己感兴趣的终点是微管,但我们的初步数据显示,心脏磷酸酶活性及其调节的持续增加几乎肯定对已建立的肥大和衰竭相关疾病机制具有更普遍的重要性,其中许多涉及肌浆网、肌原纤维、和肌丝外细胞骨架。因此,这项工作可以作为一个例子,以帮助概念化可能的机械收敛的一些迄今为止明显不同的异常肥厚和衰竭的心脏。
项目成果
期刊论文数量(1)
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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Donald R. Menick其他文献
Two Groups Control Light-Induced Schiff Base Deprotonation and the Proton Affinity of Asp<sup>85</sup> in the Arg<sup>82</sup>His Mutant of Bacteriorhodopsin
- DOI:
10.1016/s0006-3495(99)77108-0 - 发表时间:
1999-11-01 - 期刊:
- 影响因子:
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Eleonora S. Imasheva;Sergei P. Balashov;Thomas G. Ebrey;Ning Chen;Rosalie K. Crouch;Donald R. Menick - 通讯作者:
Donald R. Menick
Role of p38/Akt Signaling Pathway in the Regulation of Sodium/Calcium Exchanger Expression in Adult Cardiomyocytes
- DOI:
10.1016/j.cardfail.2010.06.077 - 发表时间:
2010-08-01 - 期刊:
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- 作者:
Olga Chernysh;Santhosh K. Mani;Donald R. Menick - 通讯作者:
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Cloning of Cardiac, Kidney, and Brain Promoters of the Feline <em>ncx1</em> Gene
- DOI:
10.1074/jbc.272.17.11510 - 发表时间:
1997-04-25 - 期刊:
- 影响因子:
- 作者:
Kimberly V. Barnes;Guangmao Cheng;Myra M. Dawson;Donald R. Menick - 通讯作者:
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Role of Nkx2.5 Acetylation by Histone Deacetylases in Regulating Sodium/Calcium Exchanger Expression in Adult Cardiomyocytes
- DOI:
10.1016/j.cardfail.2010.06.140 - 发表时间:
2010-08-01 - 期刊:
- 影响因子:
- 作者:
Mona S. Li;Santhosh K. Mani;Benjamin Addy;Thirumagal Thiagarajan;Christine B. Kern;Donald R. Menick - 通讯作者:
Donald R. Menick
Donald R. Menick的其他文献
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{{ truncateString('Donald R. Menick', 18)}}的其他基金
ShEEP application for Integrated Hypoxia Exposure and Analysis Core
用于集成缺氧暴露和分析核心的 ShEEP 应用
- 批准号:
9795680 - 财政年份:2019
- 资助金额:
$ 5.72万 - 项目类别:
Regulatory Role of HDAC in Post-MI Ventricular Remodeling
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9919999 - 财政年份:2014
- 资助金额:
$ 5.72万 - 项目类别:
Regulatory Role of HDAC in Post-MI Ventricular Remodeling
HDAC 在 MI 后心室重构中的调节作用
- 批准号:
10265359 - 财政年份:2014
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Regulatroy Role of HDAC in Post-MI Ventricular Remodeling
HDAC 在 MI 后心室重构中的调节作用
- 批准号:
8818507 - 财政年份:2014
- 资助金额:
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Regulatory Role of HDAC in Post-MI Ventricular Remodeling
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- 批准号:
10455524 - 财政年份:2014
- 资助金额:
$ 5.72万 - 项目类别:
Regulatory Role of HDAC in Post-MI Ventricular Remodeling
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- 批准号:
10830235 - 财政年份:2014
- 资助金额:
$ 5.72万 - 项目类别:
Regulatroy Role of HDAC in Post-MI Ventricular Remodeling
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- 批准号:
8975085 - 财政年份:2014
- 资助金额:
$ 5.72万 - 项目类别:
MAP4 REGULATION OF CARDIAC MICROTUBULE NETWORK DENSITY
MAP4 心脏微管网络密度的调节
- 批准号:
8235944 - 财政年份:2010
- 资助金额:
$ 5.72万 - 项目类别:
MAP4 REGULATION OF CARDIAC MICROTUBULE NETWORK DENSITY
MAP4 心脏微管网络密度的调节
- 批准号:
8490586 - 财政年份:2010
- 资助金额:
$ 5.72万 - 项目类别:
Research Education Program for Minority Medical Students
少数民族医学生研究教育计划
- 批准号:
8829317 - 财政年份:2009
- 资助金额:
$ 5.72万 - 项目类别:
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