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: 10562825
• 负责人: Jian Liu
• 金额: $ 39.79万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 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
• 来源: https://reporter.nih.gov/project-details/10562825
• 关键词: Actins; Address; Affect; Back; Behavior; Binding; Biological Process; Cell Adhesion Molecules; Cells; Chemicals; Complex; Couples; Coupling; Cytoskeleton; Data Analyses; Development; Developmental Process; Embryonic Development; Environment; Event; Experimental Designs; Experimental Models; Extracellular Matrix; Feedback; Feeds; Focal Adhesions; Generations; Goals; Individual; Integral Membrane Protein; Integrins; Link; Measures; Mechanics; Mediating; Modeling; Molecular; Monitor; Movement; Nature; Neoplasm Metastasis; Pattern; Process; Protein Dynamics; Proteins; Research; Research Personnel; Resolution; Role; Shapes; Stress Fibers; Testing; Time; Traction; Work; cell motility; chemical reaction; experimental study; grasp; in silico; infancy; insight; live cell imaging; mathematical model; mechanotransduction; multi-scale modeling; predictive modeling; preference; skills; synergism; temporal measurement; tool; transmission process; tumor; user friendly software

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.

项目概要 该提案的总体目标是建立预测性多尺度数学模型来破译 杜罗轴机制。 Durotaxis 是细胞向较硬的细胞外基质 (ECM) 迁移的偏好，并且具有 在许多生物过程中发挥重要作用，从胚胎发育到肿瘤转移。粘着斑 (FA) 是 durotaxis 的功能单位；它是一种基于整合素的多蛋白跨膜连接，细胞通过它发挥肌动蛋白 基于细胞骨架的牵引力来牵引 ECM 并感知刚度。尽管与生物医学高度相关 应用中，目前尚不清楚 FA 如何介导 ECM 刚度的机械传感并驱动 durotaxis，很大程度上 因为预测数学模型落后于该领域的描述性实验发现。在单一 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，但它们无法解释 FA 如何以及为何 局部蛋白质活动通过独特的时空模式（类似于足迹）来适应环境，这些模式是 被证明对于 durotaxis 至关重要。 FA本地化“足迹”的完整底层机制及其确切 因此，在 durotaxis 中的作用尚不清楚。此外，杜罗轴必须协调细胞体的运动和突出/缩回 细胞边缘。虽然 FA 介导的牵引力驱动细胞体，但 FA 局部机械传感事件如何协调 细胞边缘动力学未知。最后，在单细胞水平上，存在许多处于不同发育阶段的FA 随时。目前尚不清楚细胞如何整合各个 FA 的机械传感活动来驱动 durotaxis。 有意义地参与实验的预测模型是可取的，并且可能掌握着破译的关键 杜罗轴。为了实现这一目标，我们已经并将以独特的方式将数学建模与迭代对话相结合 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 介导的机械传感和 durotaxis。该提案的基础是我们之前的发现。我们 建立了第一个捕捉整个 FA 成熟过程本质的数学模型。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通量耦合到成熟的复合体 FA 将应力纤维 (SF) 介导的收缩传输到 ECM。该模型独特地链接了FA本地化的精细 蛋白质活性的特征——从 FA 成熟过程中出现——到 FA 机械传感事件。模型预测 并通过实验证实 FA 接合 SF 的伸长率和收缩性之间存在负反馈 是 FA 局部牵引振动和 ECM 刚度机械传感的基础。受到这些发现的启发，我们 具体目标是确定：1​​) FA 机械传感中 FA 力传递和 SF 伸长如何相互干扰； 2）如何 FA 机械传感影响细胞边缘突出/缩回，以及 3) 细胞如何整合单个 FA 的机械传感 驱动杜罗轴。如果成功，拟议的研究将提供一个解释数据和指导的定量平台 durotaxis 实验设计，具有从 FA 局部动力学、细胞边缘到多尺度分辨率 突出/缩回，以实现全细胞水平的细胞运动。