Theoretical modeling on mechanochemical feedbacks of cellular processes

细胞过程机械化学反馈的理论模型

• 批准号: 8344881
• 负责人: Jian Liu
• 金额: $ 121.62万
• 依托单位: NATIONAL HEART, LUNG, AND BLOOD INSTITUTE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8344881
• 关键词: Accounting; Actins; Actomyosin; Adhesions; Affinity; Anaphase; Area; Behavior; Binding; Biochemical; Biochemistry; Biology; Caenorhabditis elegans; Cell Adhesion; Cell Cycle; Cell Nucleus; Cell division; Cell membrane; Cell physiology; Cell-Cell Adhesion; Cells; Cellular biology; Centrosome; Characteristics; Chemical Dynamics; Chemistry; Chromatids; Chromosomes; Collaborations; Complex; Computer Simulation; Contracts; Couples; Coupling; Cytokinesis; Cytoplasm; Cytoskeleton; Data; Diffuse; Docking; Drosophila genus; Dynein ATPase; Embryo; Endocytosis; Environment; Event; Exhibits; Extracellular Matrix; F-Actin; Feedback; Filament; Focal Adhesion Kinase 1; Focal Adhesions; Germ; Goals; Integrins; Kinesin; Kinetochores; Liquid substance; Mechanics; Mediating; Membrane; Membrane Protein Traffic; Metaphase; Microfilaments; Microtubule Bundle; Microtubules; Mitochondria; Mitosis; Mitotic spindle; Mitotic/Spindle Checkpoint; Modeling; Morphology; Organelles; Paper; Pathway interactions; Phosphotransferases; Preparation; Process; Protein Tyrosine Kinase; Proteins; Publications; Publishing; Regulation; Research; Resistance; Role; Science; Shapes; Signal Transduction; Site; Statistical Models; Structure; Tertiary Protein Structure; Testing; Theoretical model; Time; Traction; United States National Institutes of Health; Vision; Yeasts; base; cell motility; chemical reaction; effectiveness measure; mathematical model; neuroblast; polymerization; response; sensor; simulation; synaptojanin; tomography; transmission process

1. Membrane Trafficking: In this project, we investigated the functional role of the BAR and F-BAR domain proteins in yeast endocytosis. Our research showed that cooperation between robust actin polymerization, and F-BAR and BAR domain proteins, and synaptojanin, is important for membrane scission. Spatio-temporal and functional information together with our theoretical modeling suggest the following picture of endocytosis: F-BAR proteins stabilize the endocytic site, while actin assembly and BAR proteins cooperate for invagination and scission. This paper is currently under review in PNAS. 2. Kinetochore motility: Based on the histogram of the neighboring distance between kinetochore ring along microtubule, I contructed a statistical model to differentiate whether the rings can diffuse or not. Our research shows that kinetochore ring must be highly diffusive. The paper is published in Mol. Biol. Cell. 3. Microtubule sequestration effects in mitosis: The commonly recognized mechanisms for spatial regulation inside the cell are membrane-bounded compartmentalization and biochemical association with subcellular organelles. We use computational modeling to investigate another spatial regulation mechanism mediated by the microtubule network in the cell. Our results demonstrate that the mitotic spindle can impose strong sequestration and concentration effects on molecules with binding affinity for microtubules, especially dynein-directed cargoes. The model can recapitulate the essence of three experimental observations on distinct microtubule network morphologies: the sequestration of germ plasm components by the mitotic spindles in the Drosophila syncytial embryo, the asymmetric cell division initiated by the time delay in centrosome maturation in the Drosophila neuroblast, and the diffusional block between neighboring nuclei in the Drosophila syncytial embryo. Our model thus suggests that cell cycle-dependent change in the microtubule network is critical for achieving different spatial regulation effects; that is, the microtubule network provides a spatially extensive docking platform for molecules and gives rise to a structured cytoplasm, in contrast to a free and fluid environment. This paper is currently under review in Current Biology. 4. Asymmetric Furrow ingression during cytokinesis: We construct a minimal model on the contractility of actomyosin ring during cytokinesis. Our model proposes that the local geometry of the furrow site, such as the Gaussian curvature of the membrane, could promote the alignment process of actomyosin filament, which in turn governs the efficiency of the local contractility. As the more the local actomyosin filament contracts, the larger the local Gaussian curvature would become. We show that this mechanism can quantitatively account for all the three modes of actomyosin contractility, depending on the coupling strength of the positive feedback between the local membrane curvature and actomyosin contractility. More importantly, our experimental testing corroborates several predictions unique to our model, suggesting an emergent mechanism of curvature-mediated positive feedback for cytokinetic actomyosin contractility. Furthermore, the model demonstrate that asymmetric furrow ingression is energetically more efficient, thereby suggesting a real functional role of the asymmetry in cytokinetic ring contraction. This model is the first of its kinds. This paper is currently under review in Science. 5. Force-velocity relationship of branching actin network: Actin networks, acting as an engine pushing against an external load, are fundamentally important to cell motility. A measure of the effectiveness of an engine is the velocity the engine is able to produce at a given force, the force-velocity curve. One type of force-velocity curve, consisting of a concave region where velocity is insensitive to increasing force followed by a decrease in velocity, is indicative of an adaptive response. In contrast, an engine whose velocity rapidly decays as a convex curve in response to increasing force would indicate a lack of adaptive response. Interestingly, even taken outside of a cellular context, branching actin networks have been observed to exhibit both concave and convex force-velocity curves. However, the exact mechanism that can explain both force-velocity curves is not yet known. We carried out an agent-based stochastic simulation to explore such a mechanism. Our results suggest that upon loading, branching actin networks are capable of remodeling by increasing the number filaments growing against the load. The remodeling depends not only on the biochemistry of actin filaments but is also dependent upon the time-scale of the network and the load. The model predicts that shortly after encountering resistance ( seconds), the actin network does not have enough time to remodel itself. The force-velocity relationship immediately after application of the load is therefore always convex. A concave force-velocity relationship requires network remodeling at longer time-scales ( minutes). Our model thus provides a mechanism that can account for both convex and concave force-velocity relationships observed in branching actin networks. This paper is currently under review in PNAS. 6. Mechanochemistry of focal adhesion formation: Focal adhesions are essential to mediate cell extracellular matrix (ECM) adhesion and force transmission during cell motilities, which involve the crosstalk between physical signals such as contractile forces or membrane dynamics, and chemical signaling events such as focal adhesion kinase related regulation pathways. However, the underline mechanism of the biophysical regulations of force transmission among actin cytoskeleton, cell membrane, focal complex and ECM remains poorly understood. We collaborated with Dr. Clare Waterman, and constructed a mathematical model to understand the behavior of focal adhesion complex under different experimental conditions. By integrating the cell membrane dynamics, actin network fluid dynamics, and the mechanochemistry of focal complex, the model reveals itself the capability to capture the essential characteristics of focal adhesions in cell motility. In particular, the model explains the heterogeneous traction force and tyrosine kinase activities within focal adhesions at different ECM stiffness. The model thus provides a comprehensive vision of the focal adhesion dynamics. This paper is currently in preparation for publication.

1. 膜贩运： 在这个项目中，我们研究了 BAR 和 F-BAR 结构域蛋白在酵母内吞作用中的功能作用。 我们的研究表明，强大的肌动蛋白聚合、F-BAR 和 BAR 结构域蛋白以及突触贾蛋白之间的合作对于膜断裂非常重要。 时空和功能信息与我们的理论模型一起表明了以下内吞作用的图景：F-BAR 蛋白稳定内吞位点，而肌动蛋白组装和 BAR 蛋白配合内陷和分裂。 该论文目前正在 PNAS 上进行评审。 2.着丝粒运动： 根据动粒环沿微管的相邻距离的直方图，我构建了一个统计模型来区分环是否可以扩散。 我们的研究表明动粒环一定是高度扩散的。 该论文发表在《Mol》上。生物。细胞。 3.有丝分裂中的微管隔离效应： 细胞内空间调节的普遍认识机制是膜界区室化和与亚细胞细胞器的生化关联。我们使用计算模型来研究细胞中微管网络介导的另一种空间调节机制。我们的结果表明，有丝分裂纺锤体可以对与微管具有结合亲和力的分子（特别是动力蛋白导向的货物）施加强烈​​的隔离和浓缩效应。该模型可以概括对不同微管网络形态的三个实验观察的本质：果蝇合胞体胚胎中有丝分裂纺锤体对种质成分的隔离，果蝇神经母细胞中中心体成熟时间延迟引发的不对称细胞分裂，以及果蝇中相邻细胞核之间的扩散阻滞 合胞体胚胎。因此，我们的模型表明，微管网络中细胞周期依赖性的变化对于实现不同的空间调节效应至关重要。也就是说，微管网络为分子提供了一个空间广泛的对接平台，并产生了结构化的细胞质，这与自由和流动的环境形成鲜明对比。这篇论文目前正在《当代生物学》杂志上接受审阅。 4. 胞质分裂过程中不对称的沟槽侵入： 我们构建了胞质分裂期间肌动球蛋白环收缩性的最小模型。 我们的模型提出，沟位的局部几何形状，例如膜的高斯曲率，可以促进肌动球蛋白丝的排列过程，进而控制局部收缩性的效率。 随着局部肌动球蛋白丝收缩得越多，局部高斯曲率就会变得越大。 我们表明，这种机制可以定量地解释肌动球蛋白收缩性的所有三种模式，具体取决于局部膜曲率和肌动球蛋白收缩性之间正反馈的耦合强度。 更重要的是，我们的实验测试证实了我们模型特有的几个预测，表明曲率介导的细胞因子肌动球蛋白收缩性正反馈的新兴机制。 此外，该模型表明，不对称沟进入在能量上更有效，从而表明不对称性在细胞因子环收缩中的真正功能作用。 该模型是此类模型中的第一个。 这篇论文目前正在《科学》杂志上进行审查。 5. 分支肌动蛋白网络的力-速度关系： 肌动蛋白网络充当推动外部负载的引擎，对细胞运动至关重要。发动机效率的衡量标准是发动机在给定力下能够产生的速度，即力-速度曲线。一种类型的力-速度曲线由凹区域组成，其中速度对力的增加随后速度的减小不敏感，这表明了自适应响应。相反，如果发动机的速度随着力的增加而迅速衰减为凸曲线，则表明发动机缺乏自适应响应。有趣的是，即使在细胞环境之外，也观察到分支肌动蛋白网络表现出凹形和凸形的力-速度曲线。然而，能够解释这两条力-速度曲线的确切机制尚不清楚。我们进行了基于代理的随机模拟来探索这样的机制。我们的结果表明，在加载时，分支肌动蛋白网络能够通过增加对抗负载生长的细丝数量来进行重塑。重塑不仅取决于肌动蛋白丝的生物化学，还取决于网络的时间尺度和负载。该模型预测，在遇到阻力后不久（几秒），肌动蛋白网络没有足够的时间来重塑自身。因此，施加载荷后立即的力-速度关系总是凸的。 凹力-速度关系需要在较长的时间尺度（分钟）内进行网络重构。因此，我们的模型提供了一种机制，可以解释在分支肌动蛋白网络中观察到的凸和凹力-速度关系。该论文目前正在 PNAS 上进行评审。 6. 粘着斑形成的力学化学： 粘着斑对于介导细胞运动过程中的细胞外基质 (ECM) 粘着和力传递至关重要，这涉及收缩力或膜动力学等物理信号与粘着斑激酶相关调节途径等化学信号事件之间的串扰。然而，肌动蛋白细胞骨架、细胞膜、局灶复合物和 ECM 之间力传递的生物物理调节的基本机制仍然知之甚少。我们与 Clare Waterman 博士合作，构建了一个数学模型来了解粘着斑复合物在不同实验条件下的行为。通过整合细胞膜动力学、肌动蛋白网络流体动力学和焦点复合物的机械化学，该模型揭示了捕获细胞运动中焦点粘附的基本特征的能力。特别是，该模型解释了不同 ECM 硬度下粘着斑内的异质牵引力和酪氨酸激酶活性。因此，该模型提供了粘着斑动力学的全面视图。 这篇论文目前正在准备出版。