Biophysical Control of Cell Form and Function by Single Actomyosin Stress Fibers

单个肌动球蛋白应力纤维对细胞形态和功能的生物物理控制

基本信息

  • 批准号:
    9399083
  • 负责人:
  • 金额:
    $ 29.97万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2017
  • 资助国家:
    美国
  • 起止时间:
    2017-09-01 至 2021-06-30
  • 项目状态:
    已结题

项目摘要

PROJECT SUMMARY/ABSTRACT Actomyosin stress fibers (SFs) enable cells to tense the extracellular matrix (ECM), a process key to cell shape determination, polarity, motility, and tissue morphogenesis. SFs within motile cells have been broadly classified into three specialized “subtypes” (dorsal fibers, transverse arcs, and ventral fibers) that differ in their antero-posterior location and network connectivity. In addition to driving normal tissue development and homeostasis, SFs and analogous contractile structures contribute to the invasion of tumors within tissue, a notable example of which is the perivascular infiltration of the deadly brain tumor glioblastoma multiforme (GBM). It has been hypothesized that dorsal fibers, transverse arcs, and ventral fibers tense each other and the ECM in very specific ways to govern cell shape, polarity, and motility. However, this paradigm suffers from several critical limitations. For example, it has not been directly demonstrated that each SF subtype generates tension as commonly assumed, which in turn derives from a lack of direct measurement of SF mechanical properties in living cells. Additionally, while these subtypes are broadly understood to vary in the molecular motors they contain (i.e. myosin II isoforms), we know virtually nothing about how these molecular-scale differences create the contractility differences across SF subtypes. Finally, and perhaps most importantly, it is unclear whether this subtype classification is relevant to the persistent migration of cells within tissue, particularly in disease states driven by aberrant cell migration. In this proposal we address all three of these critical open questions by combining single-cell biophotonic technologies, traditional cell and molecular biology approaches, engineered culture systems, and ex vivo tissue models. A key enabling tool for these studies (which our team has pioneered over the past decade) is femtosecond laser nanosurgery (FLN), which enables us to selectively cut single SFs in living cells, thereby allowing us to deduce both the mechanical loads borne by that SF and its structural contributions to the rest of the cell. In Aim 1, we will apply FLN to selectively incise SFs from each canonical subtype to map these mechanical properties and structural contributions. We will also combine FLN with single-cell micropatterning and fluorescence-based readouts of molecular tension to determine how single SFs distribute tension throughout the cell and contribute to EGF-dependent polarization and motility. In Aim 2, we will investigate how the stoichiometry and mechanochemical properties of specific myosin II isoforms collaborate to determine the mechanical properties of the entire SF. In Aim 3, we will combine these approaches with a microfluidic model we developed with a brain-slice paradigm to determine how specific SF subtypes and the myosin isoforms therein contribute to perivascular invasion in GBM. To our knowledge, Aim 3 studies will represent the first measurements of SF mechanics and function in mammalian tissue. In summary, this project will marry innovative single-cell and culture technologies to address major open questions surrounding the microscale, biophysical mechanisms of cell shape shape, polarity, and motility.
项目总结/文摘

项目成果

期刊论文数量(0)
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会议论文数量(0)
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Sanjay Kumar其他文献

Sanjay Kumar的其他文献

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{{ truncateString('Sanjay Kumar', 18)}}的其他基金

Mechanisms of adhesion and invasion in hyaluronic acid matrices
透明质酸基质的粘附和侵袭机制
  • 批准号:
    10185347
  • 财政年份:
    2021
  • 资助金额:
    $ 29.97万
  • 项目类别:
Mechanisms of adhesion and invasion in hyaluronic acid matrices
透明质酸基质的粘附和侵袭机制
  • 批准号:
    10380867
  • 财政年份:
    2021
  • 资助金额:
    $ 29.97万
  • 项目类别:
Mechanisms of adhesion and invasion in hyaluronic acid matrices
透明质酸基质的粘附和侵袭机制
  • 批准号:
    10605241
  • 财政年份:
    2021
  • 资助金额:
    $ 29.97万
  • 项目类别:
Cellular mechanobiology and engineering of active brown adipose tissue
活性棕色脂肪组织的细胞力学生物学和工程
  • 批准号:
    9912145
  • 财政年份:
    2019
  • 资助金额:
    $ 29.97万
  • 项目类别:
Cellular mechanobiology and engineering of active brown adipose tissue
活性棕色脂肪组织的细胞力学生物学和工程
  • 批准号:
    10415961
  • 财政年份:
    2019
  • 资助金额:
    $ 29.97万
  • 项目类别:
Cellular mechanobiology and engineering of active brown adipose tissue
活性棕色脂肪组织的细胞力学生物学和工程
  • 批准号:
    10170330
  • 财政年份:
    2019
  • 资助金额:
    $ 29.97万
  • 项目类别:
Cellular mechanobiology and engineering of active brown adipose tissue
活性棕色脂肪组织的细胞力学生物学和工程
  • 批准号:
    9747438
  • 财政年份:
    2018
  • 资助金额:
    $ 29.97万
  • 项目类别:
Biophysical Control of Cell Form and Function by Single Actomyosin Stress Fibers
单个肌动球蛋白应力纤维对细胞形态和功能的生物物理控制
  • 批准号:
    10669215
  • 财政年份:
    2017
  • 资助金额:
    $ 29.97万
  • 项目类别:
Biophysical Control of Cell Form and Function by Single Actomyosin Stress Fibers
单个肌动球蛋白应力纤维对细胞形态和功能的生物物理控制
  • 批准号:
    10445792
  • 财政年份:
    2017
  • 资助金额:
    $ 29.97万
  • 项目类别:
Biophysical Control of Cell Form and Function by Single Actomyosin Stress Fibers
单个肌动球蛋白应力纤维对细胞形态和功能的生物物理控制
  • 批准号:
    9977697
  • 财政年份:
    2017
  • 资助金额:
    $ 29.97万
  • 项目类别:

相似国自然基金

由actomyosin介导的集体性细胞迁移对唇腭裂发生的影响的研究
  • 批准号:
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  • 批准年份:
    2023
  • 资助金额:
    32 万元
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Nuclear force feedback as rheostat for actomyosin tension control
核力反馈作为肌动球蛋白张力控制的变阻器
  • 批准号:
    MR/Y001125/1
  • 财政年份:
    2024
  • 资助金额:
    $ 29.97万
  • 项目类别:
    Research Grant
CAREER: Cytokinesis without an actomyosin ring and its coordination with organelle division
职业:没有肌动球蛋白环的细胞分裂及其与细胞器分裂的协调
  • 批准号:
    2337141
  • 财政年份:
    2024
  • 资助金额:
    $ 29.97万
  • 项目类别:
    Continuing Grant
CAREER: Computational and Theoretical Investigation of Actomyosin Contraction Systems
职业:肌动球蛋白收缩系统的计算和理论研究
  • 批准号:
    2340865
  • 财政年份:
    2024
  • 资助金额:
    $ 29.97万
  • 项目类别:
    Continuing Grant
Elucidation of the mechanism by which actomyosin emerges cell chirality
阐明肌动球蛋白出现细胞手性的机制
  • 批准号:
    23K14186
  • 财政年份:
    2023
  • 资助金额:
    $ 29.97万
  • 项目类别:
    Grant-in-Aid for Early-Career Scientists
Deciphering actomyosin contractility regulation during incomplete germ cell division
破译不完全生殖细胞分裂过程中肌动球蛋白收缩性的调节
  • 批准号:
    573067-2022
  • 财政年份:
    2022
  • 资助金额:
    $ 29.97万
  • 项目类别:
    University Undergraduate Student Research Awards
CAREER: Actuating robots with actomyosin active gels
职业:用肌动球蛋白活性凝胶驱动机器人
  • 批准号:
    2144380
  • 财政年份:
    2022
  • 资助金额:
    $ 29.97万
  • 项目类别:
    Continuing Grant
Collaborative Research: Mechanics of Reconstituted Self-Organized Contractile Actomyosin Systems
合作研究:重建自组织收缩肌动球蛋白系统的力学
  • 批准号:
    2201236
  • 财政年份:
    2022
  • 资助金额:
    $ 29.97万
  • 项目类别:
    Standard Grant
Collaborative Research: Mechanics of Reconstituted Self-Organized Contractile Actomyosin Systems
合作研究:重建自组织收缩肌动球蛋白系统的力学
  • 批准号:
    2201235
  • 财政年份:
    2022
  • 资助金额:
    $ 29.97万
  • 项目类别:
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Coordination of actomyosin and anillo-septin sub-networks of the contractile ring during cytokinesis
胞质分裂过程中收缩环肌动球蛋白和 anillo-septin 子网络的协调
  • 批准号:
    463633
  • 财政年份:
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  • 批准号:
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  • 财政年份:
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  • 资助金额:
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