Altered nucleus-cytoskeleton coupling in dystrophic muscle
营养不良性肌肉中核-细胞骨架耦合的改变
基本信息
- 批准号:10615087
- 负责人:
- 金额:$ 8.33万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-01-20 至 2025-03-31
- 项目状态:未结题
- 来源:
- 关键词:AblationAccelerationActinsAdultAutomobile DrivingBiochemistryBiological AssayCell NucleusCell physiologyCellsCellular StructuresComplexCouplingCytoplasmCytoskeletonDevelopmentDiseaseDisease ProgressionDuchenne muscular dystrophyDystrophinElementsEmery-Dreifuss Muscular DystrophyEngineeringEnvironmentFluorescence Resonance Energy TransferFluorescent in Situ HybridizationFunctional disorderGene ExpressionGeneticGenetic ModelsGenetic TranscriptionGoalsGrowthHealthImpairmentInjuryInstructionIntermediate FilamentsIsometric ExerciseKnowledgeLasersLeadLinkMAPK3 geneMaintenanceManualsMarylandMeasurementMeasuresMechanical StressMechanicsMentorshipMicroscopyMicrotubule AlterationMicrotubulesModelingMolecular BiologyMovementMusMuscleMuscle WeaknessMuscle functionMuscle satellite cellMuscular AtrophyMuscular DystrophiesMusculoskeletalNuclearOrganellesPathologyPathway interactionsPatientsPhysical therapyPhysiologyPositioning AttributePost-Translational Protein ProcessingPredispositionProcessProliferatingProteinsPublishingRNARailroadsRegulator GenesRestRoleSignal PathwaySkeletal MuscleSpatial DistributionStressStretchingStructureTestingTherapeutic EffectUniversitiesWasting SyndromeWorkexperienceimprovedinsightmechanical forcemechanical signalmechanotransductionmedical schoolsmicro-dystrophinmini-dystrophinmouse modelmultidisciplinarynew therapeutic targetnovel therapeutic interventionnucleocytoplasmic transportpharmacologicprotein complexresearch facultyresponsesensorskeletal muscle wastingskillstenure tracktooltransmission process
项目摘要
Project Summary:
Duchenne muscular dystrophy (DMD), the most common and severe form of muscular dystrophy, is
characterized by progressive wasting of skeletal muscles and marked susceptibility to damage. Several
associated processes could underlie the pathology. The nucleus, a regulator of gene expression and a
mechanotransduction hub, has increased movement in mdx (murine model of DMD) muscle. Microtubules
(MTs) serve as the “railroad tracks” for cellular organelle transport, including the nucleus. The nucleus is
connected to MTs and the rest of the cytoskeleton through the LINC (linkers of nucleus and cytoskeleton)
complex. Both, MT organization and LINC complex expression are altered in dystrophic muscle. I will test the
hypothesis that nuclear instability, due to disease-driven MT network and LINC complex alterations, results in
improper myonuclear domain maintenance (with hypermobile and improperly positioned nuclei), and impaired
nuclear mechanotransduction, further driving muscle weakness and susceptibility to injury in dystrophic
muscle. In WT and mdx muscle I will measure:
1) nuclear spatial distribution & nuclear movement using time-lapse microscopy
2) myonuclear domain maintenance by measuring RNA spatial distribution of cargoed proteins using
fluorescence in-situ hybridization; and nuclear movement & global transcriptional activity following gaps in
myonuclear domain using laser ablation
3) nuclear localization of Yes- associated protein (a nuclear relay of mechanical signaling), ERK 1/2 (a key
marker of muscle growth) and FRET based nuclear strain sensors, as end points of nuclear
mechanotransduction, following passive stretch, isometric and eccentric contractions
4) myonuclear domain maintenance and nuclear mechanotransduction, following blockage of stretch
activated channels to block sarcolemmal signaling pathways
5) the above parameters using established genetic/pharmacologic manipulations to the MT network & the
LINC complex, and following mini- and micro-dystrophins that have previously shown to either fully or partially
rescue MT network and susceptibility to injury
Successful completion of this proposal will allow for the development of new avenues to improve
musculoskeletal health for patients with DMD, and potentially other dystrophies. This proposal takes place in a
multi-disciplinary environment at University of Maryland School of Medicine, with support from experts in
physical therapy, physiology, molecular biology, biochemistry, and engineering, such that I can gain skills in
cellular and muscle mechanics to move towards an independent, tenure-track research faculty position.
项目总结:
项目成果
期刊论文数量(7)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Muscle phenotype of a rat model of Duchenne muscular dystrophy.
- DOI:10.1002/mus.27061
- 发表时间:2020-12
- 期刊:
- 影响因子:3.4
- 作者:Iyer SR;Xu S;Shah SB;Lovering RM
- 通讯作者:Lovering RM
The Nucleoskeleton: Crossroad of Mechanotransduction in Skeletal Muscle.
核骨骼:骨骼肌机械转导的十字路口。
- DOI:10.3389/fphys.2021.724010
- 发表时间:2021
- 期刊:
- 影响因子:4
- 作者:Iyer SR;Folker ES;Lovering RM
- 通讯作者:Lovering RM
Alterations of neuromuscular junctions in Duchenne muscular dystrophy.
- DOI:10.1016/j.neulet.2020.135304
- 发表时间:2020-10-15
- 期刊:
- 影响因子:2.5
- 作者:Lovering RM;Iyer SR;Edwards B;Davies KE
- 通讯作者:Davies KE
Abnormalities in Brain and Muscle Microstructure and Neurochemistry of the DMD Rat Measured by in vivo Diffusion Tensor Imaging and High Resolution Localized 1H MRS.
通过体内扩散张量成像和高分辨率局部 1H MRS 测量 DMD 大鼠的大脑和肌肉微观结构和神经化学异常。
- DOI:10.3389/fnins.2020.00739
- 发表时间:2020
- 期刊:
- 影响因子:4.3
- 作者:Xu,Su;Tang,Shiyu;Li,Xin;Iyer,ShamaR;Lovering,RichardM
- 通讯作者:Lovering,RichardM
The Neuromuscular Junction: Roles in Aging and Neuromuscular Disease.
- DOI:10.3390/ijms22158058
- 发表时间:2021-07-28
- 期刊:
- 影响因子:5.6
- 作者:Iyer SR;Shah SB;Lovering RM
- 通讯作者:Lovering RM
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{{ truncateString('Shama Rajan Iyer', 18)}}的其他基金
Altered nucleus-cytoskeleton coupling in dystrophic muscle
营养不良性肌肉中核-细胞骨架耦合的改变
- 批准号:
10188430 - 财政年份:2019
- 资助金额:
$ 8.33万 - 项目类别:
Altered nucleus-cytoskeleton coupling in dystrophic muscle
营养不良性肌肉中核-细胞骨架耦合的改变
- 批准号:
10401848 - 财政年份:2019
- 资助金额:
$ 8.33万 - 项目类别:
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