Predictive multi-scale model of focal adhesion-based durotaxis

基于粘着斑的 durotaxis 的预测多尺度模型

基本信息

  • 批准号:
    10562825
  • 负责人:
  • 金额:
    $ 39.79万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2023
  • 资助国家:
    美国
  • 起止时间:
    2023-01-23 至 2026-12-31
  • 项目状态:
    未结题

项目摘要

Project Summary The over-arching goal of this proposal is to establish the predictive multi-scale mathematical model to decipher the mechanism of durotaxis. Durotaxis is the preference of cells migrating toward a stiffer extracellular matrix (ECM) and has important roles in many biological processes, ranging from embryo development to tumor metastasis. Focal adhesion (FA) is the functional unit of durotaxis; it an integrin-based multi-protein transmembrane linkage, through which cell exerts actin cytoskeleton-based traction force to tug the ECM and sense the stiffness. Despite the high relevance to biomedical applications, it is not well understood how FA mediates mechanosensing of ECM stiffness and drives durotaxis, largely because predictive mathematical models lag behind the descriptive experimental finding in the field. At single-FA level, while previous models explain molecular-clutch behaviors in FA mechanosensing, they cannot explain how and why FA- localized protein activities adapt to environments by distinctive spatial-temporal patterns (akin to footprints) that are demonstrated to be essential for durotaxis. The full underlying mechanisms of the FA-localized “footprint” and its exact roles in durotaxis are thus unknown. Further, durotaxis must coordinate movements of cell body and protrusion/retraction of cell edge. While the FA-mediated tractions drive the cell body, how the FA-localized mechanosensing events coordinate with the cell edge dynamics is unknown. Last, at a single-cell level, there exist many FAs at different developmental stages at any time. It is not understood how the cell integrates the mechanosensing activities of individual FAs to drive durotaxis. A predictive model that meaningfully engages with experiments is desirable and likely holds the key to decipher durotaxis. Toward this goal, we have been and will uniquely integrate mathematical modeling in iterative dialogues with experimental testing. The central hypothesis is: FA-localized spatial-temporal dynamics of the traction force generation and transmission defines FA-mediated mechanosensing and durotaxis. The basis of this proposal is our previous findings. We built the first mathematical model that captures the essence of entire FA maturation process. That is, FA evolves from a nascent complex, the centripetally growing FA that couples the retrograde flux of branching actin network, to the mature FA that transmits the stress fiber (SF)-mediated contractions onto ECM. This model uniquely links the FA-localized fine features of protein activities – emerging from FA maturation process – to FA mechanosensing events. The model predicted and was experimentally confirmed that a negative feedback between the elongation and contractility of the FA-engaging SF underlies the FA-localized traction oscillation and mechanosensing of ECM stiffness. Ushered by these findings, our specific aims are to determine: 1) how FA force-transmission and SF elongation cross-talk in FA mechanosensing; 2) how FA mechanosensing affects cell edge protrusion/retraction, and 3) how cell integrates mechanosensation of individual FAs to drive durotaxis. If successful, the proposed research would provide a quantitative platform interpret data and guide durotaxis experimental designs, which has the multi-scale resolutions ranging from FA-localized dynamics, cell edge protrusion/retraction, to cell movement at whole-cell level.
项目摘要 该方案的最终目标是建立预测性多尺度数学模型, 硬脊膜扩张的机制趋硬性是细胞向更硬的细胞外基质(ECM)迁移的偏好,并且具有 在从胚胎发育到肿瘤转移的许多生物学过程中起重要作用。粘着斑(FA) 是硬旋转的功能单位,它是一种基于整合素的多蛋白跨膜连接,细胞通过它产生肌动蛋白 基于ECM的牵引力来牵引ECM并感测刚度。尽管与生物医学的高度相关性 在应用中,FA如何介导ECM刚度的机械感测并在很大程度上驱动硬旋转, 因为预测性的数学模型落后于该领域的描述性实验发现。在单FA级别, 虽然以前的模型解释了FA机械传感中的分子离合器行为,但它们不能解释FA是如何以及为什么发生的。 局部蛋白质活动通过独特的时空模式(类似于足迹)适应环境, 被证明是硬脊膜扩张的关键。FA局部化“足迹”的全部潜在机制及其确切的 因此,在硬脊膜扩张中的作用是未知的。此外,硬旋转必须协调细胞体和突出/回缩的运动 细胞边缘。当FA介导的牵引力驱动细胞体时,FA定位的机械感知事件如何协调 与小区边缘的动态是未知的。最后,在单细胞水平上,不同发育阶段存在着多个脂肪酸 立即使尚不清楚细胞如何整合单个FA的机械感应活动以驱动硬旋转。 一个有意义地与实验相结合的预测模型是可取的,并且可能掌握着破译的关键。 硬脊膜扩张为了实现这一目标,我们已经并将在迭代对话中独特地整合数学建模, 实验测试中心假设是:牵引力产生的FA局部时空动力学, 传输定义了FA介导的机械感测和硬旋转。这一建议的基础是我们以前的调查结果。我们 建立了第一个数学模型,捕捉整个FA成熟过程的本质。也就是说,FA是从 新生复合体,向心生长的FA,将分支肌动蛋白网络的逆行流耦合到成熟的肌动蛋白网络。 FA将应力纤维(SF)介导的收缩传递到ECM上。该模型唯一地将FA局部化精细 蛋白质活动的特征-从FA成熟过程出现-FA机械传感事件。该模型预测 并且通过实验证实,FA接合SF的伸长和收缩之间存在负反馈, 是FA局部牵引振荡和ECM刚度的机械感测的基础。根据这些发现,我们 具体目标是确定:1)FA力传递和SF伸长如何在FA机械感测中串扰; 2)如何 FA机械感觉影响细胞边缘突出/缩回,以及3)细胞如何整合单个FA的机械感觉 来驱动硬脊膜扩张如果成功,拟议的研究将提供一个定量平台,解释数据和指导 durotaxis实验设计,它具有多尺度分辨率,从FA局部动力学,细胞边缘 突出/回缩,到全细胞水平的细胞运动。

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

Jian Liu其他文献

Jian Liu的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('Jian Liu', 18)}}的其他基金

Predictive multi-scale model of focal adhesion-based durotaxis
基于粘着斑的 durotaxis 的预测多尺度模型
  • 批准号:
    10798520
  • 财政年份:
    2023
  • 资助金额:
    $ 39.79万
  • 项目类别:
3D printing of Tungsten Radial Collimator
钨径向准直器的 3D 打印
  • 批准号:
    10004837
  • 财政年份:
    2020
  • 资助金额:
    $ 39.79万
  • 项目类别:
Portable photoacoustic microscopy
便携式光声显微镜
  • 批准号:
    7656172
  • 财政年份:
    2009
  • 资助金额:
    $ 39.79万
  • 项目类别:
Portable Fiber Lasers for Multiphoton Endoscope
用于多光子内窥镜的便携式光纤激光器
  • 批准号:
    7536162
  • 财政年份:
    2008
  • 资助金额:
    $ 39.79万
  • 项目类别:
A compact high-power ultrafast fiber laser system for high resolution and high se
紧凑型高功率超快光纤激光系统,具有高分辨率和高灵敏度
  • 批准号:
    7481349
  • 财政年份:
    2008
  • 资助金额:
    $ 39.79万
  • 项目类别:
A compact high power ultrashort femtosecond fiber laser for high resolution secon
紧凑型高功率超短飞秒光纤激光器,用于高分辨率秒
  • 批准号:
    7269228
  • 财政年份:
    2007
  • 资助金额:
    $ 39.79万
  • 项目类别:
Theoretical modeling on mechanochemical feedbacks of cellular processes
细胞过程机械化学反馈的理论模型
  • 批准号:
    9357232
  • 财政年份:
  • 资助金额:
    $ 39.79万
  • 项目类别:
Theoretical modeling on mechanochemical feedbacks of cellular processes
细胞过程机械化学反馈的理论模型
  • 批准号:
    8939857
  • 财政年份:
  • 资助金额:
    $ 39.79万
  • 项目类别:
Theoretical modeling on mechanochemical feedbacks of cellular processes
细胞过程机械化学反馈的理论模型
  • 批准号:
    8558026
  • 财政年份:
  • 资助金额:
    $ 39.79万
  • 项目类别:
Theoretical modeling on mechanochemical feedbacks of cellular processes
细胞过程机械化学反馈的理论模型
  • 批准号:
    8344881
  • 财政年份:
  • 资助金额:
    $ 39.79万
  • 项目类别:

相似海外基金

Rational design of rapidly translatable, highly antigenic and novel recombinant immunogens to address deficiencies of current snakebite treatments
合理设计可快速翻译、高抗原性和新型重组免疫原,以解决当前蛇咬伤治疗的缺陷
  • 批准号:
    MR/S03398X/2
  • 财政年份:
    2024
  • 资助金额:
    $ 39.79万
  • 项目类别:
    Fellowship
CAREER: FEAST (Food Ecosystems And circularity for Sustainable Transformation) framework to address Hidden Hunger
职业:FEAST(食品生态系统和可持续转型循环)框架解决隐性饥饿
  • 批准号:
    2338423
  • 财政年份:
    2024
  • 资助金额:
    $ 39.79万
  • 项目类别:
    Continuing Grant
Re-thinking drug nanocrystals as highly loaded vectors to address key unmet therapeutic challenges
重新思考药物纳米晶体作为高负载载体以解决关键的未满足的治疗挑战
  • 批准号:
    EP/Y001486/1
  • 财政年份:
    2024
  • 资助金额:
    $ 39.79万
  • 项目类别:
    Research Grant
Metrology to address ion suppression in multimodal mass spectrometry imaging with application in oncology
计量学解决多模态质谱成像中的离子抑制问题及其在肿瘤学中的应用
  • 批准号:
    MR/X03657X/1
  • 财政年份:
    2024
  • 资助金额:
    $ 39.79万
  • 项目类别:
    Fellowship
CRII: SHF: A Novel Address Translation Architecture for Virtualized Clouds
CRII:SHF:一种用于虚拟化云的新型地址转换架构
  • 批准号:
    2348066
  • 财政年份:
    2024
  • 资助金额:
    $ 39.79万
  • 项目类别:
    Standard Grant
The Abundance Project: Enhancing Cultural & Green Inclusion in Social Prescribing in Southwest London to Address Ethnic Inequalities in Mental Health
丰富项目:增强文化
  • 批准号:
    AH/Z505481/1
  • 财政年份:
    2024
  • 资助金额:
    $ 39.79万
  • 项目类别:
    Research Grant
ERAMET - Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
ERAMET - 快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
  • 批准号:
    10107647
  • 财政年份:
    2024
  • 资助金额:
    $ 39.79万
  • 项目类别:
    EU-Funded
BIORETS: Convergence Research Experiences for Teachers in Synthetic and Systems Biology to Address Challenges in Food, Health, Energy, and Environment
BIORETS:合成和系统生物学教师的融合研究经验,以应对食品、健康、能源和环境方面的挑战
  • 批准号:
    2341402
  • 财政年份:
    2024
  • 资助金额:
    $ 39.79万
  • 项目类别:
    Standard Grant
Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
  • 批准号:
    10106221
  • 财政年份:
    2024
  • 资助金额:
    $ 39.79万
  • 项目类别:
    EU-Funded
Recite: Building Research by Communities to Address Inequities through Expression
背诵:社区开展研究,通过表达解决不平等问题
  • 批准号:
    AH/Z505341/1
  • 财政年份:
    2024
  • 资助金额:
    $ 39.79万
  • 项目类别:
    Research Grant
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了