Core1: Computational

核心1:计算

基本信息

  • 批准号:
    10271569
  • 负责人:
  • 金额:
    $ 30.89万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2021
  • 资助国家:
    美国
  • 起止时间:
    2021-09-17 至 2026-08-31
  • 项目状态:
    未结题

项目摘要

Computational Core (Core A): SUMMARY To guide and interpret the in vitro (Project 1) and in vivo experiments (Project 2) and to provide a physical basis for changes in transcriptional patterns in response to mechanical stresses (Core B), this core will employ an array of computational tools spanning a wide range of length and time scales. These include models for cell adhesion, cytoskeletal function, cell-matrix interactions and 3D multiscale models for nuclear mechano- transduction and chromatin organization. This suite of modeling tools will reveal non-linear interactions between cell and nuclear deformation during of extravasation and migration, mechano-adaptation in response to fluid and solid stresses, intravascular and extravascular niche properties and cell death for individual compared to clustered CTCs. Significantly, modelling of 3D genome organization will allow us to elucidate the relationship between the mechanics of the cell, chromatin organization, and transcription, thus providing new insights on how mechanical stresses regulate gene expression during metastasis, and identification of reversible and persisting chromatin deformation associates with cell survival or death. Cancer cells invade individually or collectively, but the factors that govern their strategies to colonize the tissue and their ability to survive intravascular stress and extravasation are poorly understood. While the coupling between cell contractility, nuclear mechanotransduction, and adhesive interactions with the ECM and vessel wall is known to affect cell adhesion and motility, the effects of this interplay on cell survival has yet to be rigorously investigated. To elucidate the physical mechanisms involved in such regulation, we developed 3D chemo- mechanical models to describe the three-way feedback between the adhesions, the cytoskeleton, and the nucleus. The model shows local tensile stresses generated at the interface of the cell and the extracellular environment regulate the properties of the nucleus, including nuclear morphology, levels of lamin A/C, histone deacetylation and nucleo-cytoplasmic shuttling of YAP/TAZ, which in turn govern spatial chromatin organization, gene expression and the ability of the cells to survive and cope with the mechanical stresses. Building on these tools, the specific aims of this project are: · Aim 1. Predict the role of vascular flow on tumor cell arrest and survival in the intravascular niche. · Aim 2. Model the mechanochemical/molecular mechanisms of individual/collective extravasation of CTCs. · Aim 3. Predict the influence of alterations in chromatin organization and transcriptional patterns induced by intravascular stress and extravasation on the survival and growth of migrating tumor cells
计算核心(核心A):摘要 指导和解释体外(项目1)和体内实验(项目2),并提供物理基础 对于响应机械应力的转录模式的变化(核心B),该核心将采用 一系列计算工具,涵盖了广泛的长度和时间尺度。其中包括细胞模型 粘附,细胞骨架功能,细胞-基质相互作用和三维多尺度模型的核机械, 转导和染色质组织。这套建模工具将揭示 细胞和核在外渗和迁移过程中的变形,对液体和 固体应力,血管内和血管外生态位特性和细胞死亡的个人相比, 成簇的CTC。值得注意的是,3D基因组组织的建模将使我们能够阐明 之间的细胞,染色质组织和转录的机制,从而提供了新的见解如何 机械应力调节转移过程中的基因表达,并鉴定可逆和持续的 染色质变形与细胞存活或死亡有关。 癌细胞单独或集体侵入,但控制它们在组织中定植策略的因素 并且它们在血管内应激和外渗中存活的能力知之甚少。而联接器 细胞收缩性、核机械力传导和与ECM和血管壁的粘附相互作用之间的关系 已知这种相互作用会影响细胞粘附和运动,但这种相互作用对细胞存活的影响还有待严格研究。 研究了为了阐明参与这种调节的物理机制,我们开发了3D化疗药物, 机械模型来描述三种方式之间的反馈粘连,细胞骨架,和 原子核该模型显示了在细胞和细胞外基质的界面处产生的局部张应力。 环境调节细胞核的性质,包括细胞核形态、核纤层蛋白A/C水平、组蛋白 雅普/TAZ的脱乙酰化和核质穿梭,这反过来又控制了染色质的空间组织, 基因表达和细胞存活和科普机械应力的能力。根据这些 该项目的具体目标是: ·目标1。预测血管内小生境中血管流动对肿瘤细胞停滞和存活的作用。 ·目标2。模拟个体/集体外渗的机械化学/分子机制 的CTC。 目标3。预测染色质组织和转录模式改变的影响 血管内应激和血管外渗对移行性肿瘤生存和生长的影响 细胞

项目成果

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Vivek Shenoy其他文献

Vivek Shenoy的其他文献

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{{ truncateString('Vivek Shenoy', 18)}}的其他基金

Core1: Computational
核心1:计算
  • 批准号:
    10688253
  • 财政年份:
    2021
  • 资助金额:
    $ 30.89万
  • 项目类别:
Core1: Computational
核心1:计算
  • 批准号:
    10490295
  • 财政年份:
    2021
  • 资助金额:
    $ 30.89万
  • 项目类别:
Integration of elasticity, viscosity, and plasticity in cellular mechanosensing
细胞力传感中弹性、粘度和塑性的整合
  • 批准号:
    10668320
  • 财政年份:
    2020
  • 资助金额:
    $ 30.89万
  • 项目类别:
Integration of elasticity, viscosity, and plasticity in cellular mechanosensing
细胞力传感中弹性、粘度和塑性的整合
  • 批准号:
    10462741
  • 财政年份:
    2020
  • 资助金额:
    $ 30.89万
  • 项目类别:
Integration of elasticity, viscosity, and plasticity in cellular mechanosensing
细胞力传感中弹性、粘度和塑性的整合
  • 批准号:
    9973613
  • 财政年份:
    2020
  • 资助金额:
    $ 30.89万
  • 项目类别:
Integration of elasticity, viscosity, and plasticity in cellular mechanosensing
细胞力传感中弹性、粘度和塑性的整合
  • 批准号:
    10246375
  • 财政年份:
    2020
  • 资助金额:
    $ 30.89万
  • 项目类别:
Uncovering mechanical mechanisms of traumatic axonal injury
揭示创伤性轴突损伤的机械机制
  • 批准号:
    9751855
  • 财政年份:
    2016
  • 资助金额:
    $ 30.89万
  • 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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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:
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  • 项目类别:
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CAREER: Cytokinesis without an actomyosin ring and its coordination with organelle division
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    2024
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阐明肌动球蛋白出现细胞手性的机制
  • 批准号:
    23K14186
  • 财政年份:
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Deciphering actomyosin contractility regulation during incomplete germ cell division
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  • 财政年份:
    2022
  • 资助金额:
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  • 财政年份:
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  • 批准号:
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  • 财政年份:
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