Myosin light chain kinase interactions and the rate of smooth muscle activation
肌球蛋白轻链激酶相互作用和平滑肌激活率
基本信息
- 批准号:8467743
- 负责人:
- 金额:$ 47.67万
- 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:2011-06-15 至 2015-05-31
- 项目状态:已结题
- 来源:
- 关键词:ActinsAcuteAddressAffinityAsthmaBehaviorBindingBiochemicalBiological AssayBiological ModelsCalorimetryCellsChronicComplexCytoskeletonDiseaseDissociationEnvironmentEnzyme-Linked Immunosorbent AssayEnzymesFilamentGenerationsGoalsHeart failureHypertensionImageImaging TechniquesIn SituIn VitroKineticsKnowledgeLabelLeadLinkMYLK geneMaintenanceMeasurementMeasuresMechanicsMediatingModelingMolecularMolecular ConformationMovementMuscleMuscle ContractionMyosin ATPaseMyosin Light Chain KinaseMyosin Type IIOrganOutcomePhasePhosphorylationPhosphorylation SitePhosphotransferasesPhysiologicalPlayProcessProtein IsoformsProteinsRegulationRelative (related person)ResearchRoleSmooth MuscleSmooth Muscle MyocytesSmooth Muscle MyosinsSolutionsSyndromeSystemTestingThin FilamentTimeairway hyperresponsivenessbasecell motilitycrosslinkhuman diseasein vitro Modelin vivoinnovationinsightnon-muscle myosinreconstitutionsingle moleculestoichiometry
项目摘要
DESCRIPTION (provided by applicant): Smooth muscle is finely tuned to carry out mechanical functions specific to the different hollow organs and vasculature they surround. Altering the contractile behaviors of smooth muscle cells can lead to a variety of pathophysiological states, such as hypertension resulting in cardiac failure and airway hyperresponsiveness associated with asthma. Mechanisms implicated in these disease states include smooth muscle plasticity, myosin isoform shifts, and impaired regulation. In each case, the proximal cause is hypercontractility generated by a change in actin-myosin activity. Actin-myosin activity is primarily regulated through the phosphorylation of smooth muscle myosin (SMM). Specifically, phosphorylation of SMM by myosin light chain kinase (MYLK) activates actin-myosin ATPase activity and muscle contraction. In this way, the activity of SMM is directly linked to the activity of MYLK; in fact MYLK activity appears to exert tight control over smooth muscle activity. It is thus no surprise that small changes in MYLK activity have been directly linked to many chronic and acute human diseases. Yet remarkably little is known about the factors that influence MYLK activity. Our preliminary studies indicate that MYLK-SMM interactions limit MYLK activity. In this proposal we continue to test this hypothesis and determine the factors that influence MYLK- SMM interactions. We will use an in vitro model system to control the constituents of our system and use a wide range of biochemical, kinetic, and imaging techniques to simultaneously measure MLYK-SMM interactions, SMM phosphorylation, and activation of mechanics. We will use solution kinetics to establish more detailed kinetic mechanisms and cell studies to establish in vivo relevance. This proposal will provide direct measurements of the mechanisms by which MYLK tunes smooth muscle contraction in normal and disease states. Moreover, the insights developed through this proposal will extend of knowledge of how non-muscle myosin is activated in non-muscle cells.
描述(由申请人提供):平滑肌被精细调节以执行其周围不同中空器官和脉管系统特有的机械功能。改变平滑肌细胞的收缩行为可导致多种病理生理状态,例如导致心力衰竭的高血压和与哮喘相关的气道高反应性。这些疾病状态涉及的机制包括平滑肌可塑性、肌球蛋白亚型变化和调节受损。在每种情况下,近端原因是肌动蛋白-肌球蛋白活性变化引起的过度收缩。肌动蛋白-肌球蛋白活性主要通过平滑肌肌球蛋白(SMM)的磷酸化来调节。特别是,肌球蛋白轻链激酶(MYLK)对SMM的磷酸化激活肌动蛋白-肌球蛋白ATP酶活性和肌肉收缩。以这种方式,SMM的活性与MYLK的活性直接相关;事实上,MYLK活性似乎对平滑肌活性施加严格控制。因此,MYLK活性的微小变化与许多慢性和急性人类疾病直接相关也就不足为奇了。然而,对影响MYLK活性的因素知之甚少。我们的初步研究表明,MYLK-SMM相互作用限制MYLK活性。在本提案中,我们继续测试这一假设,并确定影响MYLK- SMM相互作用的因素。我们将使用体外模型系统来控制我们系统的组成部分,并使用广泛的生化,动力学和成像技术来同时测量MLYK-SMM相互作用,SMM磷酸化和力学激活。我们将使用溶液动力学来建立更详细的动力学机制,并使用细胞研究来建立体内相关性。该提案将提供MYLK在正常和疾病状态下调节平滑肌收缩的机制的直接测量。此外,通过这一提议开发的见解将扩展非肌肉肌球蛋白如何在非肌肉细胞中激活的知识。
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)
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Jonathan E. Baker其他文献
The Combined Effects of ADP, ATP, and Myosin Density on Cooperative Activation of Thin Filaments
- DOI:
10.1016/j.bpj.2009.12.850 - 发表时间:
2010-01-01 - 期刊:
- 影响因子:
- 作者:
Timothy J. O'Donnell;Jonathan E. Baker - 通讯作者:
Jonathan E. Baker
Using a Non-Averaged Displacement Analysis to Characterize Multiple Populations of Single Molecule Motions
- DOI:
10.1016/j.bpj.2011.11.3780 - 发表时间:
2012-01-31 - 期刊:
- 影响因子:
- 作者:
Michael S. Carter;Feng Hong;Christine P. Cremo;Jonathan E. Baker - 通讯作者:
Jonathan E. Baker
Jonathan E. Baker的其他文献
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{{ truncateString('Jonathan E. Baker', 18)}}的其他基金
Myosin light chain kinase interactions and the rate of smooth muscle activation
肌球蛋白轻链激酶相互作用和平滑肌激活率
- 批准号:
8677962 - 财政年份:2011
- 资助金额:
$ 47.67万 - 项目类别:
Myosin light chain kinase interactions and the rate of smooth muscle activation
肌球蛋白轻链激酶相互作用和平滑肌激活率
- 批准号:
8280310 - 财政年份:2011
- 资助金额:
$ 47.67万 - 项目类别:
The Effects of Altered Contractility on Cardiac Myocyte Signaling and Hypertrophy
收缩力改变对心肌细胞信号传导和肥大的影响
- 批准号:
8112353 - 财政年份:2011
- 资助金额:
$ 47.67万 - 项目类别:
Myosin light chain kinase interactions that influence the rate of smooth muscle a
影响平滑肌a速率的肌球蛋白轻链激酶相互作用
- 批准号:
8100106 - 财政年份:2011
- 资助金额:
$ 47.67万 - 项目类别:
The Effects of Altered Contractility on Cardiac Myocyte Signaling and Hypertrophy
收缩力改变对心肌细胞信号传导和肥大的影响
- 批准号:
8248263 - 财政年份:2011
- 资助金额:
$ 47.67万 - 项目类别:
A Multi-Scale Study of the Interplay Between Force Generating and Force Sensing M
力生成和力传感之间相互作用的多尺度研究
- 批准号:
7904008 - 财政年份:2008
- 资助金额:
$ 47.67万 - 项目类别:
A Multi-Scale Study of the Interplay Between Force Generating and Force Sensing M
力生成和力传感之间相互作用的多尺度研究
- 批准号:
8102983 - 财政年份:2008
- 资助金额:
$ 47.67万 - 项目类别:
Biochemical Screens for Modulators of Muscle Force
肌肉力量调节剂的生化筛选
- 批准号:
7532549 - 财政年份:2008
- 资助金额:
$ 47.67万 - 项目类别:
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