FIRCA: Probing the Nucleus- Cytoskeleton Connection Using Magnetic Tweezers

FIRCA:使用磁镊探测细胞核-细胞骨架连接

基本信息

  • 批准号:
    8080552
  • 负责人:
  • 金额:
    $ 5.81万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2011
  • 资助国家:
    美国
  • 起止时间:
    2011-06-01 至 2014-03-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): This research will be done primarily in Chile at the Catholic university of Chile in collaboration with Alfredo Celedon, as an extension of NIH Grant No. R01GM08420401, 09/30/08 - 08/31/12." The nuclear envelope has an internal shell called nuclear lamina, a thin meshwork of intermediate filaments composed of A- and B-type lamins. Mutations scattered along Lmna, which encodes A-type lamins, have been associated with a broad range of human diseases, collectively called laminopathies. In mammalian cells, the recent characterization of the LINC complex, an evolutionary-conserved protein complex that interacts both with the nuclear lamina and the cytoskeleton of mammalian cells suggests that nucleus and cytoskeleton are intimately connected. Our main hypothesis is that the nuclear envelope is mechanically connected to the actin filament network and the MTOC directly through specific linker proteins, including emerin and the LINC complexes, and that these connections are disrupted in laminopathies. Recent results obtained in the PI's lab suggest that the depletion of lamin A/C, as well as the specific rupture of the LINC complexes negatively affects both cell motility and intracellular mechanics. Moreover, results from a shear flow assay combined with immuno-fluorescence show that the distance between MTOC and nuclear envelope is greatly increased following emerin depletion and that this loosening of the MTOC correlates with the inability of emerin- deficient cells and lamin A/C-deficient cells to polarize in the flow direction. However, a direct demonstration that the actin cytoskeleton and the MTOC are actually both connected to the nuclear envelope and that these physical connections are mediated by the LINC complexes and emerin, respectively, is lacking. Here, we propose to use magnetic tweezers and magnetic nanorods to demonstrate the existence of these molecular connections, decipher the role of emerin and the LINC complexes in these connections and determine the mechanical strength of the links between the nucleus and both the actin filament network and the MTOC. We also use magnetic tweezers to measure for the first time the micromechanical properties of nucleus in live cells. PUBLIC HEALTH RELEVANCE: Mutations scattered along the Lmna gene, which encodes A-type lamins, are associated to a broad range of human diseases, collectively called laminopathies. Using a new, single cell magnetic tweezers strategy, the proposed research may help establish a biophysical basis for the wide variety of disease phenotypes associated to human laminopathies.
描述(由申请人提供):本研究将主要在智利的智利天主教大学进行,与Alfredo Celedon合作,作为NIH拨款号的延伸。R01gm08420401, 09/30/08 - 08/31/12。”核膜有一个叫做核层的内壳,这是一个由a型和b型层组成的中间细丝的薄网。基因突变分散在编码a型纤层蛋白的Lmna上,与广泛的人类疾病有关,这些疾病统称为纤层病。在哺乳动物细胞中,最近对LINC复合物(一种进化保守的蛋白质复合物,可与哺乳动物细胞的核层和细胞骨架相互作用)的表征表明,细胞核和细胞骨架密切相关。我们的主要假设是,核膜通过特定的连接蛋白(包括emerin和LINC复合物)直接与肌动蛋白丝网络和MTOC机械连接,并且这些连接在层状病变中被破坏。最近在PI实验室获得的结果表明,层粘连蛋白A/C的消耗以及LINC复合物的特异性破裂对细胞运动和细胞内力学都有负面影响。此外,结合免疫荧光的剪切流动实验结果显示,在emerin耗尽后,MTOC与核膜之间的距离大大增加,并且MTOC的松动与emerin缺乏细胞和层粘连蛋白a / c缺陷细胞无法在流动方向上极化有关。然而,缺乏直接证明肌动蛋白细胞骨架和MTOC实际上都与核膜相连,并且这些物理连接分别由LINC复合物和emerin介导。在这里,我们建议使用磁性镊子和磁性纳米棒来证明这些分子连接的存在,破译emerin和LINC复合物在这些连接中的作用,并确定核与肌动蛋白丝网络和MTOC之间连接的机械强度。我们还首次使用磁镊子测量了活细胞细胞核的微力学特性。

项目成果

期刊论文数量(0)
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科研奖励数量(0)
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Denis Wirtz其他文献

Denis Wirtz的其他文献

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{{ truncateString('Denis Wirtz', 18)}}的其他基金

Organ Specific Project
器官特定项目
  • 批准号:
    10531004
  • 财政年份:
    2022
  • 资助金额:
    $ 5.81万
  • 项目类别:
Organ Specific Project
器官特定项目
  • 批准号:
    10708880
  • 财政年份:
    2022
  • 资助金额:
    $ 5.81万
  • 项目类别:
Tech Core 2
技术核心2
  • 批准号:
    10532385
  • 财政年份:
    2021
  • 资助金额:
    $ 5.81万
  • 项目类别:
Center for 3D Imaging in Cancer Cell Biology
癌细胞生物学 3D 成像中心
  • 批准号:
    10375190
  • 财政年份:
    2021
  • 资助金额:
    $ 5.81万
  • 项目类别:
Tech Core 2
技术核心2
  • 批准号:
    10375193
  • 财政年份:
    2021
  • 资助金额:
    $ 5.81万
  • 项目类别:
Center for 3D Imaging in Cancer Cell Biology
癌细胞生物学 3D 成像中心
  • 批准号:
    10532378
  • 财政年份:
    2021
  • 资助金额:
    $ 5.81万
  • 项目类别:
Center for 3D Imaging in Cancer Cell Biology
癌细胞生物学 3D 成像中心
  • 批准号:
    10375191
  • 财政年份:
    2021
  • 资助金额:
    $ 5.81万
  • 项目类别:
3D Whole-Pancreas Analysis of Mouse Models of Pancreatic Cancer
胰腺癌小鼠模型的 3D 全胰腺分析
  • 批准号:
    10830513
  • 财政年份:
    2021
  • 资助金额:
    $ 5.81万
  • 项目类别:
Center for 3D Imaging in Cancer Cell Biology
癌细胞生物学 3D 成像中心
  • 批准号:
    10532377
  • 财政年份:
    2021
  • 资助金额:
    $ 5.81万
  • 项目类别:
Validation of Nuclear Morphology as a Biomarker of Aging and Aging-Related Phenotypes
核形态作为衰老和衰老相关表型生物标志物的验证
  • 批准号:
    10424439
  • 财政年份:
    2018
  • 资助金额:
    $ 5.81万
  • 项目类别:

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