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
• 负责人: Jian Liu
• 金额: $ 3.28万
• 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/10798520
• 关键词: Actins; Affect; Behavior; Biological Process; Cells; Complex; Couples; Cytoskeleton; Data Analyses; Development; Embryonic Development; Environment; Event; Experimental Designs; Experimental Models; Extracellular Matrix; Feedback; Focal Adhesions; Generations; Goals; Individual; Integral Membrane Protein; Integrins; Link; Mechanics; Mediating; Modeling; Molecular; Nature; Neoplasm Metastasis; Pattern; Process; Proteins; Research; Resolution; Role; Stress Fibers; Testing; Time; Traction; cell motility; experimental study; mathematical model; mechanotransduction; multi-scale modeling; predictive modeling; preference; transmission process; tumor

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 该提案的总体目标是建立预测性的多尺度数学模型，以破译 Durotaxis的机理。 Durotaxis是细胞偏向于较硬的细胞外基质（ECM）的偏好，并且具有 在许多生物过程中的重要作用，从胚胎发育到肿瘤转移。焦点粘附（FA） 是Durotaxis的功能单元；它是基于整合素的多蛋白跨膜链接，通过该链接执行肌动蛋白 基于细胞骨架的牵引力可以拉动ECM并感知刚度。尽管与生物医学有很高的相关性 应用，尚不清楚FA如何介导ECM刚度的机制，并驱动Durotaxis，很大程度上是 因为预测性数学模型滞后于现场的描述性实验发现。在单fa级别， 尽管以前的模型解释了FA机制中的分子离合器行为，但他们无法解释如何以及为什么FA- 局部蛋白质活性通过独特的时空模式（类似于足迹）适应环境 证明对Durotaxis至关重要。 FA定位的“足迹”的完整基础机制及其确切的 因此，在Durotaxis中的作用是未知的。此外，Durotaxis必须协调细胞体的运动和突出/缩回 细胞边缘。当FA介导的牵引力驱动细胞体时，FA定位机构如何坐标 使用细胞边缘动力学是未知的。最后，在单细胞级别，在不同的发育阶段存在许多FA 随时。它不了解细胞如何整合单个FAS的机理化活性以驱动Durotaxis。 有意义地参与实验的预测模型是可取的，并且可能是破译的关键 durotaxis。为了实现这一目标，我们一直并将在迭代对话中唯一地整合数学建模 实验测试。中心假设是：牵引力的产生和 传播定义了FA介导的机理和Durotaxis。该提案的基础是我们以前的发现。我们 构建了第一个捕获整个FA成熟过程的本质的数学模型。也就是说，FA从 新生的复合物是将分支肌动蛋白网络的逆行通量耦合到成熟的逆行通量 将应力纤维（SF）介导的收缩传递到ECM的FA。该模型独特地链接了FA局域网 蛋白质活性的特征 - 从FA成熟过程中出现到FA机理事件。该模型预测 并在实验上证实，FA参与SF的伸长和收缩性之间的负反馈 基础ECM刚度的FA定位牵引力振荡和机制。这些发现使我们的 具体目的是确定：1​​）FA机制中的FA力传输和SF伸长率如何； 2）如何 FA机制影响细胞边缘蛋白/缩回，3）细胞如何整合单个FAS的机制 驱动durotaxis。如果成功，拟议的研究将提供定量平台解释数据和指南 Durotaxis实验设计，其具有多尺度的分辨率，范围从FA定位动力学，细胞边缘 突出/缩回，向整个细胞水平的细胞运动。

项目成果

Solid-to-liquid phase transition in the dissolution of cytosolic misfolded-protein aggregates.

• DOI: 10.1016/j.isci.2023.108334
• 发表时间: 2023-12-15
• 期刊: ISCIENCE
• 影响因子: 5.8
• 作者: Tomaszewski, Alexis;Wang, Rebecca;Sandoval, Eduardo;Zhu, Jin;Liu, Jian;Li, Rong
• 通讯作者: Li, Rong