Intracellular Curvature Sensing as a Regulator of Musculoskeletal Differentiation
细胞内曲率传感作为肌肉骨骼分化的调节器
基本信息
- 批准号:9037584
- 负责人:
- 金额:$ 7.29万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2014
- 资助国家:美国
- 起止时间:2014-04-01 至 2018-03-31
- 项目状态:已结题
- 来源:
- 关键词:AdhesionsAffectAmericanAnimal ModelArchitectureB-LymphocytesBindingBiocompatible MaterialsBiologyBone TissueCaliberCellsCellular biologyComplexDevelopmentDisciplineElementsEvaluationEventExtracellular MatrixExtracellular Matrix ProteinsFiberFluorescence Resonance Energy TransferFocal AdhesionsFractureFutureGenerationsGeometryGrantGrowth Factor GeneGuidelinesHealthLigamentsMAP Kinase GeneMAPK3 geneMesenchymal Stem CellsMuscleMusculoskeletalMusculoskeletal DevelopmentNeuronsOligodendrogliaOperative Surgical ProceduresPTK2 genePatternPhenotypePhosphorylationPhosphotransferasesProceduresProteinsRegenerative MedicineReplacement ArthroplastyRoleRuptureShapesSignal TransductionSpinal FusionStem cellsTechniquesTendon structureTissuesWettabilityWritingbasebone lossclinically relevantdesignmaterials sciencemigrationnanofiberrepairedresponsescaffoldsrc-Family Kinasessuccesstissue regeneration
项目摘要
DESCRIPTION (provided by applicant): Procedures to repair bone loss, fracture non-unions, spinal fusions, total joint replacement, as well as, ruptures to tendon, ligament and muscle affect
well over 2 million Americans annually. Surgical repair techniques for all of these procedures have the potential for either incremental or revolutionary improvement through biomaterial nanofiber based strategies. The development of these musculoskeletal tissues from mesenchymal stem cells, MSCs, involves a unique niche composed of assorted extracellular matrix proteins and growth factors. Not surprising, the ECM composition is unique to the musculoskeletal tissue. Cells express approximately 150 different proteins involved in nearly 700 unique interactions, the adhesome, which they use to sense and respond to unique ECM compositions. Of all current proteins in the adhesome, three are directly involved in 36% of all kinase interactions in the adhesome, FAK, Src and Fyn. This proposal seeks to make clear the aspects of adhesion signaling leading to altered phenotype involved with MSC attachment to nanofibers presenting a range of diameters. Understanding how the geometry of the underlying substrate alters the localization and activation of adhesion related proteins will provide design criteria enabling the generation of synthetic MSC niche's capable of directed differentiation down musculoskeletal lineages. Future biomaterial substrates cannot ignore the role that simple aspects such as shape have on directing progenitor cells to the target tissue. This grant seeks to merge the disciplines of regenerative medicine, materials science and cell biology to determine a mechanism by which MSCs sense and respond to the curvature of a nanofiber leading to altered phenotype and ultimately altered lineage commitment down musculoskeletal lineages. Preliminary evidence in support of this grant has indicated that there is a correlation between fiber diameter and focal adhesion size/maturity. The fiber diameters corresponding to the largest adhesions also demonstrated increased RhoA activity and cytoskeletal stiffness. Additionally, nanofiber diameter demonstrated a correlation over MAPK activity, indicating a possible connection to lineage commitment. Specific Aim 1 will produce nanofiber substrates that demonstrate a range of diameters from 1.5¿m to 500nm; while maintaining consistency with all other geometric parameters of a nanofiber substrate and will examine the binding of FAK to either Src or Fyn. Specific Aim 2 examines the unique phenotype present on each fiber diameter, i.e. migration, proliferation and lineage commitment. Specific Aim 3 seeks to bring together the previous two aims and correlate the nanofiber diameter dependent alterations in FAK/Src-family kinase binding and activation with the altered phenotypes observed. Successful completion of this proposal will provide design guidelines for future biomaterial architectures and
advance biology through identification of an intracellular curvature sensing mechanism.
描述(由申请人提供):修复骨丢失、骨折不愈合、脊柱融合、全关节置换以及肌腱、韧带和肌肉损伤破裂的手术
每年超过200万美国人。所有这些手术的外科修复技术都有可能通过基于生物材料的策略进行增量或革命性的改进。从间充质干细胞(MSC)发育这些肌肉骨骼组织涉及由各种细胞外基质蛋白和生长因子组成的独特生态位。毫不奇怪,ECM组合物对于肌肉骨骼组织是独特的。细胞表达大约150种不同的蛋白质,涉及近700种独特的相互作用,即粘附体,它们用于感知和响应独特的ECM成分。在粘附体中的所有当前蛋白质中,三种直接参与粘附体中36%的所有激酶相互作用,FAK,Src和Fyn。该提案旨在明确粘附信号传导的各个方面,这些方面导致与MSC附着到呈现一系列直径的纳米纤维有关的表型改变。了解底层基质的几何形状如何改变粘附相关蛋白的定位和激活,将提供设计标准,使合成MSC生态位的产生能够定向分化肌肉骨骼谱系。未来的生物材料基质不能忽视简单的方面,如形状对引导祖细胞到靶组织的作用。该资助旨在合并再生医学,材料科学和细胞生物学的学科,以确定MSC感知和响应导致表型改变并最终改变肌肉骨骼谱系的谱系承诺的弯曲的机制。支持该资助的初步证据表明,纤维直径与焦点粘合尺寸/成熟度之间存在相关性。纤维直径对应于最大的粘连也表现出增加的RhoA活性和细胞骨架刚度。此外,血管直径与MAPK活性相关,表明可能与谱系定型有关。特异性目标1将产生直径范围为1.5 μ m至500 nm的荧光素底物;同时与荧光素底物的所有其他几何参数保持一致,并将检查FAK与Src或Fyn的结合。特定目标2检查每个纤维直径上存在的独特表型,即迁移、增殖和谱系定型。具体目标3试图将前两个目标结合在一起,并将FAK/Src家族激酶结合和活化中的直径依赖性改变与观察到的改变的表型相关联。该提案的成功完成将为未来的生物材料架构提供设计指南,
通过识别细胞内曲率传感机制来推进生物学。
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)
Nanofiber curvature with Rho GTPase activity increases mouse embryonic fibroblast random migration velocity.
- DOI:10.1093/intbio/zyab022
- 发表时间:2021-12
- 期刊:
- 影响因子:0
- 作者:D. T. Bowers;Justin L. Brown
- 通讯作者:D. T. Bowers;Justin L. Brown
Geometry sensing through POR1 regulates Rac1 activity controlling early osteoblast differentiation in response to nanofiber diameter.
- DOI:10.1039/c4ib00225c
- 发表时间:2015-02
- 期刊:
- 影响因子:0
- 作者:Higgins AM;Banik BL;Brown JL
- 通讯作者:Brown JL
3D Near-Field Electrospinning of Biomaterial Microfibers with Potential for Blended Microfiber-Cell-Loaded Gel Composite Structures.
- DOI:10.1002/adhm.201700456
- 发表时间:2017-10
- 期刊:
- 影响因子:10
- 作者:Fattahi P;Dover JT;Brown JL
- 通讯作者:Brown JL
Molecular mechanisms orchestrating the stem cell response to translational scaffolds.
协调干细胞对翻译支架反应的分子机制。
- DOI:10.1109/embc.2015.7318716
- 发表时间:2015
- 期刊:
- 影响因子:0
- 作者:Ozdemir,Tugba;Higgins,AndrewM;Brown,JustinL
- 通讯作者:Brown,JustinL
Multiscale Poly-(ϵ-caprolactone) Scaffold Mimicking Nonlinearity in Tendon Tissue Mechanics.
- DOI:10.1007/s40883-016-0008-5
- 发表时间:2016-03-01
- 期刊:
- 影响因子:2.6
- 作者:Banik BL;Lewis GS;Brown JL
- 通讯作者:Brown JL
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Justin L. Brown其他文献
The Pull of Tissue Engineering: A STEM Outreach Program with a Modular Cyclic Stretch Device to Engage High School Students
组织工程的吸引力:利用模块化循环拉伸装置吸引高中生的 STEM 推广计划
- DOI:
10.1007/s43683-021-00053-0 - 发表时间:
2021 - 期刊:
- 影响因子:0
- 作者:
Tugba Ozdemir;Erdal Şenocak;G. Gerber;Seçil Erden Tayhan;Justin L. Brown - 通讯作者:
Justin L. Brown
Platinum equation of state to greater than two terapascals: Experimental data and analytical models
大于 2 兆帕的铂状态方程:实验数据和分析模型
- DOI:
- 发表时间:
2021 - 期刊:
- 影响因子:3.7
- 作者:
K. Cochrane;P. Kalita;Justin L. Brown;C. A. McCoy;J. Gluth;H. Hanshaw;E. Scoglietti;M. Knudson;S. Rudin;S. Crockett - 通讯作者:
S. Crockett
Tissue Engineering Approaches to Recapitulate the Micro- and Macro-architecture of the Knee Meniscus
- DOI:
10.1007/s40883-025-00411-2 - 发表时间:
2025-04-17 - 期刊:
- 影响因子:1.900
- 作者:
Alyssa K. Salazar;Justin L. Brown - 通讯作者:
Justin L. Brown
Effects of urbanization on resource use and individual specialization in coyotes (Canis latrans) in southern California
城市化对南加州土狼(Canis latrans)资源利用和个体专业化的影响
- DOI:
10.1371/journal.pone.0228881 - 发表时间:
2020 - 期刊:
- 影响因子:3.7
- 作者:
Rachel N. Larson;Justin L. Brown;T. Karels;S. Riley - 通讯作者:
S. Riley
Scaling Law for the Onset of Solidification at Extreme Undercooling.
极端过冷时凝固开始的缩放定律。
- DOI:
- 发表时间:
2023 - 期刊:
- 影响因子:8.6
- 作者:
P. C. Myint;D. Sterbentz;Justin L. Brown;B. Stoltzfus;J. P. Delplanque;J. Belof - 通讯作者:
J. Belof
Justin L. Brown的其他文献
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{{ truncateString('Justin L. Brown', 18)}}的其他基金
Intracellular Curvature Sensing as a Regulator of Musculoskeletal Differentiation
细胞内曲率传感作为肌肉骨骼分化的调节器
- 批准号:
8704613 - 财政年份:2014
- 资助金额:
$ 7.29万 - 项目类别:
Migratory Morphology: A Function of Fibrous Extracellular Matrix Geometry Sensing
迁移形态:纤维细胞外基质几何传感的功能
- 批准号:
8824068 - 财政年份:2014
- 资助金额:
$ 7.29万 - 项目类别:
Intracellular Curvature Sensing as a Regulator of Musculoskeletal Differentiation
细胞内曲率传感作为肌肉骨骼分化的调节器
- 批准号:
8812780 - 财政年份:2014
- 资助金额:
$ 7.29万 - 项目类别:
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