Microscale Stochastic Modeling of Biological Mechanics

生物力学的微尺度随机模型

• 批准号: 0635535
• 负责人: Paul Atzberger
• 金额: --
• 依托单位: University of California-Santa Barbara
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-01 至 2009-08-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=0635535&HistoricalAwards=false
• 关键词: Microscale; Stochastic; Modeling; Biological; Mechanics

In this research project a general mathematical framework and computational method are developed which extend the Immersed Boundary Method to account for thermal fluctuations. The thermal fluctuations are taking into account by including appropriate stochastic forcing terms in the fluid equations. These methods are then applied to study the dynamic membrane rearrangements involved in the functions of two cell organelles, the Golgi Apparatus and Mitochondria. The main biological questions that are addressed concern the role that membrane geometry and spatial distribution of biochemical species play in the functions of these organelles, as induced by the membrane biochemistry, osmotic stresses, fluid flow, and thermal fluctuations. With advances in biochemical assays and electron tomography data is now becoming available which hint at how these cell organelles function both in healthy and in diseased cells. While a comprehensive understanding remains elusive, mathematical modeling may help clarify our present understanding and aid in postulating basic mechanisms by which these cell organelles function. The detailed, large-scale mathematical modeling of this project is intended to shed light on some of these mechanisms, by generating and refining experimentally testable hypothesis about cell organelles' dynamical structures. This work may also advance our understanding of cell organelle processes in general, and possibly give insight into the cellular mechanisms which break down during diseased states suggesting new medical intervention strategies. In addition to contributing to basic science, the knowledge gained in this research will be used in training graduate students and postdoctoral researchers, and in the design of research-influenced mathematical biology courses for which materials will be posted on the web. Software packages will also be made available for the general computational methods developed.With advances in cell biology compelling information has been obtained about many cellular processes from mathematical models which consider primarily the interactions between a collection of biochemical species. An even deeper understanding may become possible if in addition the spatial organization of these components and their interactions with cellular structures are modeled. In this project the role cellular structures play through spatial distribution of biochemical species is studied, with a specific emphasis on modeling at a coarse-level the Golgi Apparatus and Mitochondria cell organelles. The mechanics of many cellular structures can be regarded at a coarse-level as flexible structures which interact with a fluid. This common mechanical feature of biological systems presents many challenges in formulating models which are amenable to mathematical analysis and computational simulation while being realistic enough to capture relevant features of the biological phenomena being studied. The Immersed Boundary Method, a computational method simultaneously accounting for flexible structures and fluid, has been used to perform simulations of these mechanical features in the study of a variety of biological systems, including blood flow around valves in the beating heart, wave propagation in the cochlea, and lift generation in insect flight. Simulating cellular processes at microscopic scales presents further challenges requiring that thermal fluctuations be taking into account for the fluid and immersed structures.

在这项研究项目中，开发了一个通用的数学框架和计算方法，它扩展了浸没边界法来计算热波动。 通过在流体方程中加入适当的随机强迫项来考虑热波动。 这些方法，然后应用于研究动态膜重排涉及的两个细胞器，高尔基体和线粒体的功能。 所解决的主要生物学问题涉及的作用，膜的几何形状和空间分布的生化物种发挥这些细胞器的功能，诱导的膜生物化学，渗透应力，流体流动，和热波动。 随着生物化学测定和电子断层扫描数据的进步，现在可以获得这些细胞器如何在健康和患病细胞中发挥作用的提示。 虽然全面的理解仍然难以捉摸，但数学建模可能有助于澄清我们目前的理解，并有助于假设这些细胞器发挥作用的基本机制。 该项目的详细，大规模的数学建模旨在通过生成和细化关于细胞器动态结构的实验可检验的假设来阐明其中一些机制。 这项工作也可能促进我们对细胞器过程的理解，并可能深入了解在疾病状态下分解的细胞机制，从而提出新的医疗干预策略。 除了有助于基础科学，在这项研究中获得的知识将用于培训研究生和博士后研究人员，并在研究影响的数学生物学课程的设计，材料将张贴在网上。 随着细胞生物学的进步，从数学模型中获得了关于许多细胞过程的令人信服的信息，这些模型主要考虑生物化学物种之间的相互作用。 如果对这些成分的空间组织及其与细胞结构的相互作用进行建模，甚至可能有更深入的理解。 在这个项目中，细胞结构通过生化物种的空间分布发挥的作用进行了研究，特别强调在一个粗略的水平上建模的高尔基体和线粒体细胞器。 许多细胞结构的力学可以在粗略的水平上被认为是与流体相互作用的柔性结构。 生物系统的这种共同的机械特征在制定模型方面提出了许多挑战，这些模型既适合数学分析和计算模拟，又足够逼真，能够捕捉所研究的生物现象的相关特征。 浸没边界法是一种同时考虑柔性结构和流体的计算方法，已被用于在各种生物系统的研究中对这些机械特征进行模拟，包括心脏跳动中瓣膜周围的血流、耳蜗中的波传播和昆虫飞行中的升力产生。 在微观尺度上模拟细胞过程提出了进一步的挑战，需要考虑流体和浸没结构的热波动。