Mechanics of lamellipodial stability, turning and self-polarization

片状足稳定性、转动和自极化的力学

• 批准号: 8668806
• 负责人: ALEXANDER MOGILNER
• 金额: $ 6.97万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8668806
• 关键词: Actins; Actomyosin; Address; Adhesions; Area; Atherosclerosis; Behavior; Biochemical Pathway; Biological; Cell Shape; Cells; Cellular biology; Characteristics; Chronic; Complex; Computer Simulation; Congenital Heart Defects; Contracts; Coupled; Cytoskeleton; Data; Defect; Development; Diagnostic; Disease; Environment; Epithelial; Equation; Equilibrium; Equipment and supply inventories; Experimental Models; Feedback; Fishes; Gel; Geometry; Goals; Growth; Immune response; Inflammatory; Intuition; Investigation; Knowledge; Lead; Locomotion; Measures; Mechanics; Membrane; Micromanipulation; Modeling; Molecular; Molecular Machines; Movement; Myosin ATPase; Neoplasm Metastasis; Physiological; Physiological Processes; Process; Proteins; Role; Shapes; Simulate; Speed; Surface; System; Testing; Therapeutic; Tissues; Traction; Variant; Vesicle; Work; Wound Healing; appendage; base; cancer cell; cell motility; clinical application; data modeling; density; kinematics; mathematical model; models and simulation; multi-scale modeling; neurodevelopment; neuronal cell body; novel; polarized cell; prospective; protein distribution; research study; tool

DESCRIPTION (provided by applicant): Cell motility goes in steps - protrusion, graded adhesion, contraction and forward translocation of the cell body. In general, protrusion is based on growth of actin arrays, adhesion depends on rapid dynamics of adhesion proteins, and myosin tendency to contract actin gel leads to the forward translocation. Cells move through diverse environments by employing many types of motile appendages and locomotory behaviors. We concentrate on the well studied motile appendage called lamellipodium - thin branched actin-myosin network deployed by many cells on flat surfaces. In the lamellipodium, molecular processes self-organize into a complex molecular machine executing a coherent mechanical action. As a result of decades of intense study, molecular inventory and general principles of steady lamellipodial locomotion are becoming clear. However, crucial physiological processes of wound healing, metastasis and tissue development require elucidation of unsteady cell movements. Besides physiological and clinical applications, quantitative understanding of such movements is a fundamental problem of cell biology and a critical test of our fledgling knowledge of active self-organizing cytoskeleton. Specifically, there is little understanding of how cells initiate motility, turning and splitting. Though there is a significant role for biochemical pathways regulating these processes, we aim to understand their mechanics by studying fish epithelial keratocytes that have an advantage of smooth integration of the motility steps. Computational modeling is an indispensable tool of discovery, so we propose a modeling/experimental investigation of the unsteady movements. Preliminary data and modeling hint that interdependence of force-generating protein distributions and cell movement and geometry underlies cell polarization, turning and splitting. Specifically, we hypothesize that the mechanism of motility initiation is a positive feedback in which the weakening of adhesion at the prospective rear of an initially symmetric cell causes local increase of actin flow, which further increases adhesion breakage. This feedback leads to irreversible asymmetric flows and re-distribution of myosin, actin and adhesions that polarize the cell. Similarly, asymmetric release of adhesions at the cell rear coupled with graded actin turnover and skewed actin flow creates a positive feedback generating cell turning. Finally, we hypothesize that having excess membrane or insufficient actin causes increased inherent fluctuations of actin density in the cell amplified by myosin-generated instabilities leading to uneven protrusions and to cell splitting. We will test these hypotheses by developing models of the viscoelastic contractile actomyosin network in the moving-boundary lamellipodium. We will simulate continuous deterministic and stochastic discrete models and predict key proteins' distributions, flows and forces, as well as cell shapes and speeds. We will calibrate and test the models by comparing the predictions with data obtained from wild type and perturbed cells. This work will result in advanced understanding of cell motility, and will also produce broadly applicable novel mathematical tools as well as mathematical model components that can be integrated with existing models of cell migration.

描述（由申请人提供）：细胞运动以步骤进行 - 突出，分级粘附，收缩和细胞体的正向易位。通常，突出基于肌动蛋白阵列的生长，粘附取决于粘附蛋白的快速动力学，而肌球蛋白倾向肌动蛋白凝胶会导致正向易位。细胞通过采用多种类型的运动附属物和运动行为来穿越各种环境。我们专注于被许多细胞在平坦表面上部署的薄型肌动蛋白 - 肌动蛋白网络的良好研究的运动附属物。在层状地位中，分子过程会自组织成一个复杂的分子机，执行相干的机械作用。经过数十年的激烈研究，稳定层状运动的分子库存和一般原理变得越来越清楚。然而，伤口愈合，转移和组织发育的关键生理过程需要阐明不稳定的细胞运动。除了生理和临床应用外，对这种运动的定量理解是细胞生物学的基本问题，也是对我们对主动自组织细胞骨架知识知识的批判性检验。 具体而言，对细胞如何启动运动，转动和分裂几乎没有理解。尽管调节这些过程的生化途径具有重要作用，但我们旨在通过研究鱼皮角化细胞，从而了解其机制，这些角膜细胞具有平稳整合运动步骤的优势。计算建模是必不可少的发现工具，因此我们提出了对不稳定运动的建模/实验研究。 初步数据和建模暗示，要产生力的蛋白质分布以及细胞运动和几何形状的相互依赖性是细胞极化，转弯和分裂的基础。具体而言，我们假设运动起始机理是一种积极的反馈，其中最初对称细胞的前瞻性后部粘附的弱化会导致肌动蛋白流动的局部增加，从而进一步增加了粘附破裂。这种反馈导致不可逆的不对称流以及肌球蛋白，肌动蛋白和粘附的重新分布，使细胞极化。同样，细胞后部粘附的不对称释放与渐变的肌动蛋白周转和偏斜的肌动蛋白流相结合会产生阳性的反馈产生细胞转动。最后，我们假设肌动蛋白过多或肌动蛋白不足会导致肌动蛋白密度的固有波动增加，从而通过肌球蛋白生成的不稳定性扩增，从而导致突起不均匀和细胞分裂。我们将通过在移动边界层状植物中开发粘弹性收缩肌球蛋白网络的模型来检验这些假设。我们将模拟连续的确定性和随机离散模型，并预测关键蛋白的分布，流和力以及细胞形状和速度。我们将通过将预测与从野生型和扰动细胞获得的数据进行比较来校准和测试模型。 这项工作将导致对细胞运动的深入了解，还将生成广泛适用的新型数学工具以及可以与现有细胞迁移模型集成的数学模型组件。