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Mechanics of lamellipodial stability, turning and self-polarization

片状足稳定性、转动和自极化的力学

基本信息

批准号：
8724511
负责人：
ALEXANDER MOGILNER
金额：
$ 46.65万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-07-01 至 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8724511
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

项目摘要

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）：细胞运动分步骤进行-细胞体的突出，分级粘附，收缩和向前移位。一般来说，突出是基于肌动蛋白阵列的生长，粘附依赖于粘附蛋白的快速动力学，肌球蛋白倾向于收缩肌动蛋白凝胶导致向前易位。细胞通过使用多种类型的运动附属物和运动行为在不同的环境中移动。我们集中研究了一种被称为板状基的运动附属物，它是由许多细胞在平面上分布的细分支肌动蛋白-肌球蛋白网络。在片层基中，分子过程自组织成一个复杂的分子机器，执行连贯的机械动作。经过几十年的深入研究，稳定板足运动的分子清单和一般原理逐渐清晰起来。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，对这些运动的定量理解是细胞生物学的一个基本问题，也是对我们对主动自组织细胞骨架的新知识的关键考验。具体来说，人们对细胞如何启动运动、转动和分裂知之甚少。尽管生物化学途径在调节这些过程中起着重要作用，但我们的目标是通过研究具有平滑整合运动步骤优势的鱼类上皮角质细胞来了解其机制。计算建模是一种不可缺少的发现工具，因此我们提出对非定常运动进行建模和实验研究。初步数据和模型提示，产生力的蛋白质分布与细胞运动和几何结构之间的相互依赖是细胞极化、转向和分裂的基础。具体来说，我们假设运动启动的机制是一种正反馈，其中最初对称的细胞前侧粘附减弱导致局部肌动蛋白流量增加，从而进一步增加粘附断裂。这种反馈导致不可逆的不对称流动和肌凝蛋白、肌动蛋白和粘连的重新分配，使细胞极化。类似地，细胞后方不对称的黏附释放，加上肌动蛋白的分级周转和肌动蛋白的倾斜流动，产生了一个正反馈，产生细胞转动。最后，我们假设膜过多或肌动蛋白不足会导致细胞内肌动蛋白密度的固有波动增加，而肌球蛋白产生的不稳定性会放大，从而导致不均匀的突起和细胞分裂。我们将通过在移动边界板基上建立粘弹性收缩肌动球蛋白网络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，并预测关键蛋白质的分布，流动和力，以及细胞的形状和速度。我们将通过比较野生型和扰动细胞的预测数据来校准和测试模型。这项工作将导致对细胞运动的深入了解，也将产生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。