Modeling bi-directional signaling and cytoskeletal dynamics in 3D cell migrations

模拟 3D 细胞迁移中的双向信号传导和细胞骨架动力学

• 批准号: 8477823
• 负责人: FRANK B GERTLER
• 金额: $ 65.24万
• 依托单位: BOSTON UNIVERSITY (CHARLES RIVER CAMPUS)
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-16 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8477823
• 关键词: Actins; Adhesions; Area; Biochemical; Biochemical Pathway; Biological Process; Biology; Biomechanics; Biophysics; Cell Communication; Cell model; Cell physiology; Cell-Matrix Junction; Cells; Cellular Structures; Complex; Computer Simulation; Coupling; Cues; Cytoskeletal Modeling; Cytoskeleton; Data; Development; Disease; Engineering; Environment; Epidermal Growth Factor; Event; Extracellular Matrix; F-Actin; Family; Gap Junctions; Goals; Growth Factor; Immigration; In Vitro; Kinetics; Knowledge; Light; Lung Neoplasms; Malignant Epithelial Cell; Malignant Neoplasms; Malignant neoplasm of lung; Mammary Neoplasms; Mechanics; Mediating; Microfluidics; Modeling; Molecular; Motion; Motor Activity; Nature; Neoplasm Metastasis; Pathway interactions; Patients; Physiological Processes; Plant Roots; Population Dynamics; Process; Prognostic Marker; Property; Protein Isoforms; Proteins; Quantitative Microscopy; RNA Splicing; Receptor Activation; Research; Rheology; Role; Signal Transduction; Staging; Stimulus; System; Testing; Time; Translating; Tumor Cell Invasion; Work; base; cell motility; clinically relevant; crosslink; genetic regulatory protein; improved; in vivo; insight; malignant breast neoplasm; meetings; member; migration; multi-scale modeling; neoplastic cell; novel; prognostic; public health relevance; research study; response; sound; success; therapeutic target; tumor progression; vasodilator-stimulated phosphoprotein; viscoelasticity

DESCRIPTION (provided by applicant): Cellular structure and function, in healthy and diseased systems, is regulated by the interaction of cells with the underlying and surrounding three-dimensional extra-cellular matrix. These complex biochemical and biomechanical interactions, independently, are well known to regulate tumor progression, invasion and metastasis. For example, the aberrant response of cells to biochemical and biophysical stimuli in metastatic breast cancer is often initiated by engagement of the cytoskeletal machinery. As such, actin interacting proteins are found at the nexus of signaling network crosstalk between biochemical and adhesion-promoting cues. One such example is Mena, a member of the Ena/VASP family of actin regulatory proteins, which has been characterized for aberrant cell-signaling response during invasion and metastasis. However, how the altered signaling network is translated into the mechanical processes, and how are these sub-cellular mechanical processes then converted into whole cell migration in 3D environments remain largely elusive. Here, based on our preliminary data, we hypothesize that increased tumor cell invasiveness in 3D environments, is governed by coupling aberrant molecular level signaling events to molecular, macromolecular and cellular biomechanical processes. Our primary goal in this proposal is to rigorously test our hypothesis by bridging the knowledge gap between in vitro signaling studies at the molecular level, and molecular mechanical and cellular models in 3D, and test the predictions of our models through quantitative experiments in 3D environments. We plan to develop and validate our cellular models using the following three specific aims: Aim I: Develop an integrated subcellular model of cytoskeletal viscoelasticity and intracellular signaling in native like 3D matrices. Aim II: Develop a quantitative model of cell migration, in 3D matrices, utilizing results from the subcellular model of Aim I. Aim III: Validate results of Aims I and II b quantifying how signaling acts cooperatively with cellular mechanics machinery and extracellular matrix properties to regulate cell migration in 3D. All three aims build upon strong preliminary data in both computation and experimental studies and will provide both fundamental insights into the coupling between mechanical and biochemical pathways and integration of information from sub-cellular structures to the cellular level. At the same time, the focus on 3D environments will create new and physiologically relevant knowledge about cellular systems in native like environments. Finally, novel platforms developed through this work will be able to test clinically relevant hypotheses and help in quantitatively understanding complex multi-scale processes during various stages of cancer progression.

描述（由申请人提供）：在健康和患病系统中，细胞结构和功能受细胞与基础和周围三维细胞外基质的相互作用的调节。这些复杂的生化和生物力学相互作用是独立的，众所周知可以调节肿瘤进展，侵袭和转移。例如，细胞对转移性乳腺癌的生化和生物物理刺激的异常反应通常是通过细胞骨架机械的参与而引发的。因此，在生物化学和促进粘附线索之间的信号网络串扰的联系中发现了肌动蛋白相互作用的蛋白。一个例子是MENA，MENA是肌动蛋白调节蛋白的ENA/VASP家族的成员，在入侵和转移过程中，其特征在于异常的细胞信号反应。但是，如何将变化的信号网络转化为机械过程，然后如何在3D环境中转换为全细胞迁移的这些亚细胞机械过程仍然难以捉摸。在这里，根据我们的初步数据，我们假设在3D环境中肿瘤细胞的侵入性提高，它通过将异常分子水平信号事件与分子，大分子和细胞生物力学过程耦合。 该提案中我们的主要目标是通过弥合分子水平的体外信号研究之间的知识差距，以及3D中的分子力学和细胞模型，并通过3D环境中的定量实验来测试我们模型的预测。我们计划使用以下三个特定目的来开发和验证我们的细胞模型：目标I：开发一个综合的细胞骨架粘弹性和​​细胞内信号传导模型 在本地人像3D矩阵一样。 AIM II：在3D矩阵中开发一个细胞迁移的定量模型， 利用AIM I的亚细胞模型的结果III III：验证目标I和II B的结果，量化信号如何与细胞力学机械和细胞外基质特性合作起作用，以调节3D中的细胞迁移。这三个目标都基于计算和实验研究的强大初步数据，并将提供对机械和生化途径之间耦合的基本见解，以及从亚细胞结构到细胞水平的信息的整合。同时，对3D环境的重点将创建有关本地类似环境中细胞系统的新的和生理上相关的知识。最后，通过这项工作开发的新型平台将能够检验临床相关的假设，并有助于定量了解癌症进展的各个阶段的复杂多尺度过程。