Calcium Regulation in the Progression of Muscular Dystrophy
肌营养不良症进展中的钙调节
基本信息
- 批准号:8436127
- 负责人:
- 金额:$ 23.21万
- 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:2011-02-18 至 2016-01-31
- 项目状态:已结题
- 来源:
- 关键词:ActinsAddressAffectAnimal ModelAnimalsAntsBiological AssayBreedingCalciumCellsCharacteristicsCodeComplexConfocal MicroscopyCouplingCytoskeletonDataDefectDevelopmentDuchenne muscular dystrophyDystroglycanDystrophinEpithelial CellsEventExtracellular MatrixExtracellular SpaceFiberFoundationsGenerationsGenesGoalsHereditary DiseaseHomeostasisImageIn VitroInstructionKnowledgeLamininLinkMeasurementMediatingMediator of activation proteinMembraneMentorsMethodsMicroscopicMolecularMuscleMuscle CellsMuscle FibersMuscular DystrophiesMutationMyopathyPLA2G6 genePathologyPathway interactionsPatientsPhasePhenotypePhospholipasePhospholipase A2PreparationRegulationResearchRoleSeveritiesSignal TransductionSkeletal MuscleSmooth Muscle MyocytesStressStriated MusclesStructureTestingTrainingUnited Statesbaseextracellularinsightlink proteinmdx mousemouse modelmuscle degenerationpatch clampreagent testingresearch studyresponse
项目摘要
Duclienne muscular dystrophy is a common genetic disorder resulting from mutations within the dystrophin
gene. It is likely that the dystrophic phenotype does not result directly from alteration to the myofibrillar
Structures, rather it is a disruption of sarcolemmal membrane integrity that nomnally confers tight control of
intracellular Ca homeostasis, which leads to elevated intracellular Ca and eventual muscle degeneration.
The pathophysiological mechanism responsible for elevation of intracellular Ca levels is not dear, however
our recent findings suggest that store-operated Ca entry (SOCE) linked to uncontrolled Ca spark activity may
contribute to the aberrant Ca influx observed in dystrophic muscle. While the mechanism of SOCE activation
is still a matter of intensive study, it has been recently detemnined that the Ca insensitive phospholipase A2
(iPLA2) is an important mediator of SOCE. The focus of this project is to test the hypothesis that aben-ant Ca
spark activity acts as a trigger for SOCE and thus induces a dystrophic cascade in mammalian skeletal
muscle through a pathway that involves iPLA2 mediated signaling. We will test this with three specific aims:
Aim 1; To establish induced Ca sparks as a trigger for SOCE in healthy and dystrophic muscle. We will
utilize multiple methods for measurement of SOCE to examine alteration to Ca entry in dystrophic fiber.
Patch-clamp measurement and modulation of Oa influx will provide insight into SR Ca release and the
activation of SOCE in dystrophic fibers. Aim 2: Detemiine the contribution of iPLA2 activity to Ca influx in
muscular dystrophy. We will examine the altered characteristics of iPLA2 function in dystrophic muscle using
various in vitro molecular and pharmacological methods. Aim 3: To elucidate if SOCE facilitates the
dystrophic cascade in skeletal muscle. Due to the inability to assess changes in the dystrophic phenotype in
skeletal muscle we wili modulate SOCE in dystrophic animals and assay changes in dystrophic
phenotypes.
杜克莱恩肌营养不良症是一种常见的遗传性疾病,由肌营养不良蛋白内的突变引起
基因。营养不良表型很可能不是由肌原纤维的改变直接导致的
结构,更确切地说,它是肌膜完整性的破坏,通常赋予对肌膜完整性的严格控制
细胞内 Ca 稳态,导致细胞内 Ca 升高并最终导致肌肉退化。
然而,导致细胞内 Ca 水平升高的病理生理机制尚不明确。
我们最近的研究结果表明,与不受控制的 Ca 火花活动相关的商店操作的 Ca 进入 (SOCE) 可能
导致营养不良肌肉中观察到的异常 Ca 流入。而SOCE激活机制
仍然是一个深入研究的问题,最近确定Ca不敏感磷脂酶A2
(iPLA2) 是 SOCE 的重要中介。该项目的重点是检验以下假设:aben-ant Ca
Spark 活动作为 SOCE 的触发因素,从而在哺乳动物骨骼中诱导营养不良级联反应
通过涉及 iPLA2 介导的信号传导的途径来控制肌肉。我们将通过三个具体目标对此进行测试:
目标1;建立诱导钙火花作为健康和营养不良肌肉中 SOCE 的触发因素。我们将
利用多种方法测量 SOCE 来检查营养不良纤维中 Ca 进入的变化。
膜片钳测量和 Oa 流入调节将提供对 SR Ca 释放和
营养不良纤维中 SOCE 的激活。目标 2:确定 iPLA2 活性对 Ca2+ 流入的贡献
肌肉萎缩症。我们将使用以下方法检查营养不良性肌肉中 iPLA2 功能的改变特征:
各种体外分子和药理学方法。目标 3:阐明 SOCE 是否促进了
骨骼肌营养不良级联反应。由于无法评估营养不良表型的变化
我们将调节营养不良动物的骨骼肌并测定营养不良动物的骨骼肌变化
表型。
项目成果
期刊论文数量(5)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Analysis of osmotic stress induced Ca2+ spark termination in mammalian skeletal muscle.
分析哺乳动物骨骼肌中渗透应激诱导的 Ca2 火花终止。
- DOI:
- 发表时间:2013
- 期刊:
- 影响因子:1.4
- 作者:Ferrante,Christopher;Szappanos,Henrietta;Csernoch,László;Weisleder,Noah
- 通讯作者:Weisleder,Noah
Dysferlin, annexin A1, and mitsugumin 53 are upregulated in muscular dystrophy and localize to longitudinal tubules of the T-system with stretch.
Dysferlin、膜联蛋白 A1 和 mitsugumin 53 在肌营养不良症中表达上调,并定位于具有拉伸作用的 T 系统纵向小管。
- DOI:10.1097/nen.0b013e31821350b0
- 发表时间:2011-04
- 期刊:
- 影响因子:3.2
- 作者:Waddell LB;Lemckert FA;Zheng XF;Tran J;Evesson FJ;Hawkes JM;Lek A;Street NE;Lin P;Clarke NF;Landstrom AP;Ackerman MJ;Weisleder N;Ma J;North KN;Cooper ST
- 通讯作者:Cooper ST
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Noah Weisleder其他文献
Noah Weisleder的其他文献
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{{ truncateString('Noah Weisleder', 18)}}的其他基金
Membrane repair as a therapeutic intervention for treating Becker Muscular Dystrophy
膜修复作为治疗贝克尔肌营养不良症的治疗干预措施
- 批准号:
10761285 - 财政年份:2023
- 资助金额:
$ 23.21万 - 项目类别:
Translational development of recombinant protein therapeutic for LGMD2B
LGMD2B 重组蛋白治疗剂的转化开发
- 批准号:
10483343 - 财政年份:2022
- 资助金额:
$ 23.21万 - 项目类别:
Optimizing membrane repair for the treatment of Duchenne muscular dystrophy
优化膜修复治疗杜氏肌营养不良症
- 批准号:
9910186 - 财政年份:2019
- 资助金额:
$ 23.21万 - 项目类别:
Calcium Regulation in the Progression of Muscular Dystrophy
肌营养不良症进展中的钙调节
- 批准号:
8230611 - 财政年份:2011
- 资助金额:
$ 23.21万 - 项目类别:
Calcium Regulation in the Progression of Muscular Dystrophy
肌营养不良症进展中的钙调节
- 批准号:
8073247 - 财政年份:2011
- 资助金额:
$ 23.21万 - 项目类别:
Calcium Regulation in the Progression of Muscular Dystrophy
肌营养不良症进展中的钙调节
- 批准号:
7532263 - 财政年份:2008
- 资助金额:
$ 23.21万 - 项目类别:
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