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.
项目摘要:
杜氏肌营养不良症(DMD)是最常见和最严重的肌营养不良症,
以骨骼肌的逐渐萎缩和对损伤的明显敏感性为特征。几
相关的过程可能是病理学的基础。细胞核是基因表达的调节器,
mechanotransduction hub,在mdx(DMD的鼠模型)肌肉中具有增加的运动。微管
(MTs)充当细胞器运输的“铁路”,包括细胞核。细胞核是
通过LINC(细胞核和细胞骨架的连接体)连接到MT和细胞骨架的其余部分
复杂. MT组织和LINC复合体表达在营养不良的肌肉中均发生改变。我将测试
假设由于疾病驱动的MT网络和LINC复合体改变而导致的核不稳定性,
不适当的肌电域维持(具有过度移动和不适当定位的核),以及受损
核机械转导,进一步驱动肌无力和易受损伤的营养不良
肌肉.在WT和mdx肌肉中,我将测量:
1)用延时显微镜观察核的空间分布和核的运动
2)通过测量运载蛋白的RNA空间分布来维持myocardial结构域,
荧光原位杂交;以及核运动和全球转录活性的缺口
使用激光烧蚀的肌层结构域
3)Yes相关蛋白(机械信号的核中继),ERK 1/2(一个关键的
肌肉生长的标志物)和基于FRET的核应变传感器,作为核应变的终点。
被动牵张、等长收缩和离心收缩后的机械传导
4)牵张阻断后肌纤维结构域的维持和核机械转导
激活通道阻断肌膜信号通路
5)上述参数使用已建立的遗传/药理学操作的MT网络和
LINC复合物,以及先前已显示完全或部分抑制
急救MT网络与损伤易感性
成功完成这项提案将有助于开发新的途径,
DMD患者的肌肉骨骼健康,以及潜在的其他营养不良。该提案发生在一个
马里兰州医学院的多学科环境,在专家的支持下,
物理治疗,生理学,分子生物学,生物化学和工程学,这样我就可以获得技能,
细胞和肌肉力学走向一个独立的,终身制的研究教师的位置。
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
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Shama Rajan Iyer其他文献
Shama Rajan Iyer的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ 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:
相似海外基金
EXCESS: The role of excess topography and peak ground acceleration on earthquake-preconditioning of landslides
过量:过量地形和峰值地面加速度对滑坡地震预处理的作用
- 批准号:
NE/Y000080/1 - 财政年份:2024
- 资助金额:
$ 8.33万 - 项目类别:
Research Grant
Collaborative Research: FuSe: R3AP: Retunable, Reconfigurable, Racetrack-Memory Acceleration Platform
合作研究:FuSe:R3AP:可重调、可重新配置、赛道内存加速平台
- 批准号:
2328975 - 财政年份:2024
- 资助金额:
$ 8.33万 - 项目类别:
Continuing Grant
SHINE: Origin and Evolution of Compressible Fluctuations in the Solar Wind and Their Role in Solar Wind Heating and Acceleration
SHINE:太阳风可压缩脉动的起源和演化及其在太阳风加热和加速中的作用
- 批准号:
2400967 - 财政年份:2024
- 资助金额:
$ 8.33万 - 项目类别:
Standard Grant
Market Entry Acceleration of the Murb Wind Turbine into Remote Telecoms Power
默布风力涡轮机加速进入远程电信电力市场
- 批准号:
10112700 - 财政年份:2024
- 资助金额:
$ 8.33万 - 项目类别:
Collaborative R&D
Collaborative Research: FuSe: R3AP: Retunable, Reconfigurable, Racetrack-Memory Acceleration Platform
合作研究:FuSe:R3AP:可重调、可重新配置、赛道内存加速平台
- 批准号:
2328973 - 财政年份:2024
- 资助金额:
$ 8.33万 - 项目类别:
Continuing Grant
Collaborative Research: FuSe: R3AP: Retunable, Reconfigurable, Racetrack-Memory Acceleration Platform
合作研究:FuSe:R3AP:可重调、可重新配置、赛道内存加速平台
- 批准号:
2328972 - 财政年份:2024
- 资助金额:
$ 8.33万 - 项目类别:
Continuing Grant
Collaborative Research: FuSe: R3AP: Retunable, Reconfigurable, Racetrack-Memory Acceleration Platform
合作研究:FuSe:R3AP:可重调、可重新配置、赛道内存加速平台
- 批准号:
2328974 - 财政年份:2024
- 资助金额:
$ 8.33万 - 项目类别:
Continuing Grant
Collaborative Research: A new understanding of droplet breakup: hydrodynamic instability under complex acceleration
合作研究:对液滴破碎的新认识:复杂加速下的流体动力学不稳定性
- 批准号:
2332916 - 财政年份:2024
- 资助金额:
$ 8.33万 - 项目类别:
Standard Grant
Collaborative Research: A new understanding of droplet breakup: hydrodynamic instability under complex acceleration
合作研究:对液滴破碎的新认识:复杂加速下的流体动力学不稳定性
- 批准号:
2332917 - 财政年份:2024
- 资助金额:
$ 8.33万 - 项目类别:
Standard Grant
Study of the Particle Acceleration and Transport in PWN through X-ray Spectro-polarimetry and GeV Gamma-ray Observtions
通过 X 射线光谱偏振法和 GeV 伽马射线观测研究 PWN 中的粒子加速和输运
- 批准号:
23H01186 - 财政年份:2023
- 资助金额:
$ 8.33万 - 项目类别:
Grant-in-Aid for Scientific Research (B)