ActuAtor, a molecular tool for generating force in living cells

ActuAtor,一种在活细胞中产生力的分子工具

基本信息

  • 批准号:
    10473892
  • 负责人:
  • 金额:
    $ 32.75万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2020
  • 资助国家:
    美国
  • 起止时间:
    2020-09-01 至 2023-08-31
  • 项目状态:
    已结题

项目摘要

PROJECT SUMMARY Mechanical force regulates diverse cellular events including vesicular trafficking and gene expression. Previous studies on mechanoresponses have focused on events taking place at the cell surface, because available techniques are limited to exert force mostly from outside of cells. We therefore propose to develop and advance a methodology termed ActuAtor that can generate force in living cells in a controlled manner. ActuAtor is based on induced accumulation of an engineered, bacteria-derived actin nucleator at a desired subcellular location, leading to force generation through polymerized actin. A first generation ActuAtor probe successfully deformed intracellular structures including organelles such as mitochondria and nucleus. To assess the biological applicability of ActuAtor, we propose to implement the technique in cells to address the form-function interplay of organelles. Intracellular organelles take various shapes and sizes. It has long been suspected that this variability relates to their functions. However, the causal relationship between their shape and function remains largely unknown, primarily due to a lack of techniques to directly manipulate the organelle morphology. By adapting ActuAtor to a model organelle, mitochondria, we will reveal how mitochondrial morphology determines their functions. Use of ActuAtor in a physiologically relevant setting will also bring about information helpful for further improvement from its original molecular design. The key innovation of our proposal is development, advancement and implementation of a cutting-edge technique to tackle a fundamental biological question that cannot otherwise be addressed with conventional techniques alone. Despite many existing molecular tools that can affect “biochemical” reactions, our genetically- encoded ActuAtor tools present one of the very few examples of enabling “physical” manipulation, namely force generation, in a live-cell environment, thus constituting high significance. This unique interdisciplinary study integrated by the PI whose expertise lies in molecular technology development as a collaboration with a mitochondria biologist, Dr. Hiromi Sesaki, is expected to generate synergy in developing molecular tools that has bona fide utility in broad cell biology experiments. As the molecular design of ActuAtor is modular, their application is not limited to mitochondria or cultured cells. Rather, they are readily applicable to other intracellular organelles such as endoplasmic reticulum and nucleus, as well as model animals such as flies and mice, which illuminates one of the exciting future directions of our research.
项目概要 机械力调节多种细胞事件,包括囊泡运输和基因表达。以前的 关于机械反应的研究主要集中在细胞表面发生的事件,因为可用 技术仅限于主要从细胞外部施加力。因此,我们建议开发和推进 一种称为 ActuAtor 的方法,可以以受控方式在活细胞中产生力。执行器基于 诱导工程化的、源自细菌的肌动蛋白成核剂在所需的亚细胞位置的积累, 导致通过聚合肌动蛋白产生力。第一代ActuAtor探针成功变形 细胞内结构包括线粒体和细胞核等细胞器。 为了评估 ActuAtor 的生物学适用性,我们建议在细胞中实施该技术来解决 细胞器的形式-功能相互作用。细胞内细胞器具有各种形状和大小。早已是 怀疑这种变异性与它们的功能有关。然而,它们的形状之间存在因果关系。 功能仍然很大程度上未知,主要是由于缺乏直接操纵细胞器的技术 形态学。通过使 ActuAtor 适应模型细胞器线粒体,我们将揭示线粒体如何 形态决定了它们的功能。在生理相关环境中使用 ActuAtor 也会带来 有助于进一步改进其原始分子设计的信息。 我们提案的关键创新是尖端技术的开发、推进和实施 解决传统技术无法解决的基本生物学问题的技术 单独的技术。尽管许多现有的分子工具可以影响“生化”反应,但我们的基因- 编码的 ActuAtor 工具提供了极少数实现“物理”操纵的示例之一,即力 在活细胞环境中生成,因此具有很高的意义。这种独特的跨学科研究 由专门从事分子技术开发的 PI 与 线粒体生物学家 Hiromi Sesaki 博士预计将在开发分子工具方面产生协同作用 在广泛的细胞生物学实验中具有真正的实用性。由于 ActuAtor 的分子设计是模块化的,因此它们 应用不限于线粒体或培养细胞。相反,它们很容易应用于其他细胞内 内质网、细胞核等细胞器,以及果蝇、小鼠等模型动物, 阐明了我们研究的令人兴奋的未来方向之一。

项目成果

期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Defunctionalizing intracellular organelles such as mitochondria and peroxisomes with engineered phospholipase A/acyltransferases.
  • DOI:
    10.1038/s41467-022-31946-5
  • 发表时间:
    2022-07-29
  • 期刊:
  • 影响因子:
    16.6
  • 作者:
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Takanari Inoue其他文献

Takanari Inoue的其他文献

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{{ truncateString('Takanari Inoue', 18)}}的其他基金

Decoding dynamic interplay between signaling and membranes in chemotaxis bymolecular actuators
通过分子致动器解码趋化中信号传导和膜之间的动态相互作用
  • 批准号:
    10846921
  • 财政年份:
    2023
  • 资助金额:
    $ 32.75万
  • 项目类别:
Decoding dynamic interplay between signaling and membranes in chemotaxis by molecular actuators
通过分子致动器解码趋化中信号传导和膜之间的动态相互作用
  • 批准号:
    10623376
  • 财政年份:
    2023
  • 资助金额:
    $ 32.75万
  • 项目类别:
ActuAtor, a molecular tool for generating force in living cells
ActuAtor,一种在活细胞中产生力的分子工具
  • 批准号:
    10246255
  • 财政年份:
    2020
  • 资助金额:
    $ 32.75万
  • 项目类别:
Feedback and Crosstalk in Eukaryotic Chemotaxis
真核趋化中的反馈和串扰
  • 批准号:
    9767252
  • 财政年份:
    2018
  • 资助金额:
    $ 32.75万
  • 项目类别:
Feedback and Crosstalk in Eukaryotic Chemotaxis
真核趋化中的反馈和串扰
  • 批准号:
    10207662
  • 财政年份:
    2018
  • 资助金额:
    $ 32.75万
  • 项目类别:
Feedback and Crosstalk in Eukaryotic Chemotaxis
真核趋化中的反馈和串扰
  • 批准号:
    9923130
  • 财政年份:
    2018
  • 资助金额:
    $ 32.75万
  • 项目类别:
Flow sensation by kidney cells
肾细胞的血流感觉
  • 批准号:
    9043873
  • 财政年份:
    2014
  • 资助金额:
    $ 32.75万
  • 项目类别:
Feedback and Crosstalk in Eukaryotic Chemotaxis- Administrative Supplement
真核趋化性中的反馈和串扰-行政补充
  • 批准号:
    8703909
  • 财政年份:
    2010
  • 资助金额:
    $ 32.75万
  • 项目类别:
Feedback and Crosstalk in Eukaryotic Chemotaxis
真核趋化中的反馈和串扰
  • 批准号:
    8109302
  • 财政年份:
    2010
  • 资助金额:
    $ 32.75万
  • 项目类别:
Feedback and Crosstalk in Eukaryotic Chemotaxis
真核趋化中的反馈和串扰
  • 批准号:
    8477210
  • 财政年份:
    2010
  • 资助金额:
    $ 32.75万
  • 项目类别:

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