Biophysical mechanisms of mechanical tension sensing at cellular integrin complexes

细胞整合素复合物机械张力传感的生物物理机制

基本信息

  • 批准号:
    8800174
  • 负责人:
  • 金额:
    $ 28.82万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2015
  • 资助国家:
    美国
  • 起止时间:
    2015-05-01 至 2019-01-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Our goal is to discover the molecular mechanisms by which integrins sense and transduce mechanical cues. Integrins are heterodimeric transmembrane proteins that link the cell's cytoskeleton to the extracellular matrix (ECM). Cells use integrins to migrate, exert force on their surroundings, and to sense the physical properties of the ECM. This latter property, termed mechanotransduction, is particularly important in human health and disease. Physical tension transmitted through integrins activates intracellular signaling that in turn exerts profound effects on processes as diverse as immune function, stem cell differentiation, and cancer cell metastasis. Despite this great physiological and medical importance, the physical mechanisms by which integrins sense mechanical force are not known. We aim to close this fundamental gap in our understanding of cell biology. In published work, we have developed F�rster resonance energy transfer (FRET) based molecular tension sensors (MTSs) that report on the mechanical tensions experienced by individual integrins in living cells. We have since combined MTSs and superresolution light microscopy to, for the first time, map force transmission within integrin adhesions with nanometer spatial resolution. The qualitatively new capabilities of MTS-based imaging allow us to tackle two fundamental questions in integrin biology that until now could not be directly addressed. In Aim 1, we will determine the physical mechanisms by which integrins sense mechanical tension. In particular, we will examine the overarching hypothesis that different integrin classes sense tension via fundamentally different mechanisms, and that these differences allow the cell to sense mechanical stimuli over a wide range of forces and timescales. In Aim 2, we will characterize the force transducing and sensing machinery in micron-sized integrin assemblies, termed focal adhesions (FAs), for the first time. Specifically, we will test the hypothesis that FAs contain highly coordinated, force-sensing microdomains, a prediction that cannot be tested using conventional techniques. This work will transform our understanding of cellular mechanotransduction by uncovering the molecular assemblies and biophysical mechanisms by which cells sense and transduce mechanical signals. More broadly, the mechano-responsiveness and compositional complexity that characterize FAs are also present in many other cellular structures. The conceptual and technical approaches developed in this project have the capacity to transform multiple fields of research by introducing powerful new single-molecule biophysical measurements in the context of intact, living cells.
描述(由申请人提供):我们的目标是发现整合素感知和消除机械信号的分子机制。整合素是连接细胞骨架与细胞外基质(ECM)的异二聚体跨膜蛋白。细胞使用整合素迁移,对其周围环境施加力,并感知ECM的物理性质。后一种性质,称为机械转导,在人类健康和疾病中特别重要。通过整合素传递的物理张力激活细胞内信号传导,进而对免疫功能、干细胞分化和癌细胞转移等多种过程产生深远影响。 尽管整合素在生理和医学上具有重要意义,但其感知机械力的物理机制尚不清楚。我们的目标是缩小我们对细胞生物学理解的这一根本差距。在已发表的工作中,我们开发了基于Fürster共振能量转移(FRET)的分子张力传感器(MTS),该传感器报告了活细胞中单个整合素所经历的机械张力。此后,我们将MTS和超分辨率光学显微镜相结合,首次以纳米空间分辨率映射整合素粘连内的力传递。 基于MTS的成像的定性新功能使我们能够解决整合素生物学中的两个基本问题,这两个问题到目前为止还无法直接解决。在目标1中,我们将确定整合素感知机械张力的物理机制。特别是,我们将研究一个总体假设,即不同的整合素类别通过根本不同的机制感知张力,并且这些差异允许细胞在广泛的力和时间尺度上感知机械刺激。在目标2中,我们将首次描述微米级整合素组件(称为粘着斑(FA))中的力转换和传感机制。具体来说,我们将测试的假设,FA包含高度协调,力传感微区,预测不能使用传统技术进行测试。这项工作将通过揭示细胞感知和识别机械信号的分子组装和生物物理机制来改变我们对细胞机械转导的理解。更广泛地说,表征FA的机械反应性和组成复杂性也存在于许多其他细胞结构中。该项目开发的概念和技术方法有能力通过在完整活细胞的背景下引入强大的新单分子生物物理测量来改变多个研究领域。

项目成果

期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
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Alexander R Dunn其他文献

Bill Weis (1959-2023): Pioneering structural biologist and biochemist who revolutionized our understanding of cell adhesion and Wnt signaling.
Bill Weis (1959-2023):结构生物学家和生物化学家先驱,彻底改变了我们对细胞粘附和 Wnt 信号传导的理解。
  • DOI:
  • 发表时间:
    2024
  • 期刊:
  • 影响因子:
    7.8
  • 作者:
    M. Peifer;Alexander R Dunn
  • 通讯作者:
    Alexander R Dunn

Alexander R Dunn的其他文献

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{{ truncateString('Alexander R Dunn', 18)}}的其他基金

Molecular mechanisms underlying force transduction at cellular adhesion complexes
细胞粘附复合物力传导的分子机制
  • 批准号:
    10221729
  • 财政年份:
    2019
  • 资助金额:
    $ 28.82万
  • 项目类别:
Molecular mechanisms underlying force transduction at cellular adhesion complexes
细胞粘附复合物力传导的分子机制
  • 批准号:
    9926286
  • 财政年份:
    2019
  • 资助金额:
    $ 28.82万
  • 项目类别:
Molecular mechanisms underlying force transduction at cellular adhesion complexes
细胞粘附复合物力传导的分子机制
  • 批准号:
    10437720
  • 财政年份:
    2019
  • 资助金额:
    $ 28.82万
  • 项目类别:
Molecular mechanisms underlying force transduction at cellular adhesion complexes
细胞粘附复合物力传导的分子机制
  • 批准号:
    10667312
  • 财政年份:
    2019
  • 资助金额:
    $ 28.82万
  • 项目类别:
Bio-AFM for combined light and atomic force imaging
用于组合光和原子力成像的生物原子力显微镜
  • 批准号:
    9074870
  • 财政年份:
    2016
  • 资助金额:
    $ 28.82万
  • 项目类别:
Molecular mechanisms underlying force sensing at intercellular junctions
细胞间连接处力传感的分子机制
  • 批准号:
    9281753
  • 财政年份:
    2016
  • 资助金额:
    $ 28.82万
  • 项目类别:
Molecular mechanisms underlying flow sensing in lymphatic endothelial cells
淋巴内皮细胞流量传感的分子机制
  • 批准号:
    8946731
  • 财政年份:
    2015
  • 资助金额:
    $ 28.82万
  • 项目类别:
Biophysical mechanisms of mechanical tension sensing at cellular integrin complexes
细胞整合素复合物机械张力传感的生物物理机制
  • 批准号:
    9229049
  • 财政年份:
    2015
  • 资助金额:
    $ 28.82万
  • 项目类别:
Understanding force-dependent binding of alpha-catenin to actin
了解 α-连环蛋白与肌动蛋白的力依赖性结合
  • 批准号:
    8964322
  • 财政年份:
    2015
  • 资助金额:
    $ 28.82万
  • 项目类别:
Understanding force-dependent binding of alpha-catenin to actin
了解 α-连环蛋白与肌动蛋白的力依赖性结合
  • 批准号:
    9144812
  • 财政年份:
    2015
  • 资助金额:
    $ 28.82万
  • 项目类别:

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张力蛋白如何将粘着斑转化为纤维状粘连并相分离以形成新的粘连信号中枢。
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