MSM-Multi-scale Analysis of Cellular Force Transmission and Biochemical Activatio

MSM-细胞力传递和生化激活的多尺度分析

• 批准号: 7032555
• 负责人: ROGER D KAMM
• 金额: $ 29.85万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-01 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7032555
• 关键词: biological signal transduction; cell migration; chemical kinetics; computer simulation; computer system design /evaluation; conformation; crosslink; method development; molecular dynamics; nonblood rheology

DESCRIPTION (provided by applicant): Numerous cellular processes occur at the interface between mechanics and biology. Such responses can range from changes in cell morphology to activation of signaling cascades to changes in cell phenotype. Although the biochemical signaling pathways activated by mechanical stimulus have been extensively studied, little is known of the basic mechanisms by which mechanical force is transduced into a biochemical signal, or how the cell changes its behavior or properties in response to external or internal stresses. While the approach proposed here has a computational emphasis, ongoing experiments will help to motivate and validate the computational studies. For example, studies have examined the change in internal structure that occurs when a neutrophil enters a capillary. An immediate reduction in stiffness is observed, followed by a progressive increase, sometimes leading to active protrusion. Mechanical deformation in this example initiates remodeling of the cell interior, activating signaling pathways that may or may not lead to a migratory response. Another example involves biochemically mediated reorganization of the intermediate filament network in the Panc-1 human pancreatic cancer cell which results in a 3-fold reduction in the stiffness of the cell and a marked increase in the hysteresis in mechanical deformation; both of these factors are considered to facilitate cell mobility and cancer metastasis. The ultimate goal in this research is to capture such phenomena through quantitative modeling and simulation and use the results in developing new insights into the disease process and ultimately, new therapies. The primary aim of this project is to develop a broad but rigorous computational framework that links mechanical forces to conformational changes in single proteins by coupling biochemical activity with molecular dynamics simulations of protein deformation in a fully three-dimensional (3D) filamentous network. The prototypical problem is the simulation of cytoskeletal rheology and remodeling. Our specific aims are to: 1. Develop separate computational approaches at the nano-, meso-, and macro-scales, using molecular dynamics, Brownian dynamics, and finite element methods to simulate the mechanical and biochemical activity responsible for cytoskeletal rheology. 2. Construct and make available to the research community multi-scale algorithms that enable direct communication between the different computational platforms. 3. Extend this simple model to incorporate multiple reactions and to include the effects of signaling pathways necessary for models of mechanotransduction and cell migration. 4. Conduct experiments in reconstituted actin networks to provide a pheonological basis for evaluation and evalidation of the computational models.

描述(申请人提供)：许多细胞过程发生在力学和生物学的交界处。这种反应的范围可以从细胞形态的变化到信号级联的激活，再到细胞表型的变化。虽然机械刺激激活的生化信号通路已经得到了广泛的研究，但对于机械力转化为生化信号的基本机制，或者细胞如何改变其行为或性质以响应外部或内部压力，人们知之甚少。虽然这里提出的方法侧重于计算，但正在进行的实验将有助于激励和验证计算研究。例如，研究已经检查了中性粒细胞进入毛细血管时发生的内部结构变化。可以观察到僵硬立即减少，然后逐渐增加，有时会导致主动突出。在这个例子中，机械变形启动了细胞内部的重塑，激活了可能导致或可能不导致迁移反应的信号通路。另一个例子涉及生物化学介导的人胰腺癌细胞PANC-1中中间丝网络的重组，导致细胞硬度降低3倍，机械变形滞后显着增加；这两个因素都被认为有助于细胞移动和癌症转移。这项研究的最终目标是通过定量建模和模拟来捕捉这些现象，并使用结果来开发对疾病过程的新见解，并最终开发新的治疗方法。该项目的主要目标是开发一个广泛但严格的计算框架，通过将生化活性与全三维(3D)丝状网络中蛋白质变形的分子动力学模拟相结合，将机械力与单个蛋白质的构象变化联系起来。最典型的问题是细胞骨架流变学和重塑的模拟。我们的具体目标是：1.在纳米、介观和宏观尺度上发展不同的计算方法，使用分子动力学、布朗动力学和有限元方法来模拟负责细胞骨架流变学的机械和生化活动。2.构建并向研究界提供多尺度算法，以实现不同计算平台之间的直接通信。3.扩展这个简单的模型以包含多种反应，并包括机械转导和细胞迁移模型所需的信号通路的影响。4.在重组的肌动蛋白网络中进行实验，为计算模型的评价和评估提供现象学基础。