Modeling Transport in Complex Intracellular Environments

复杂细胞内环境中的运输建模

• 批准号: 1616926
• 负责人: Ajay Gopinathan
• 金额: $ 26万
• 依托单位: University of California - Merced
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-01 至 2021-05-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1616926&HistoricalAwards=false
• 关键词: Modeling; Transport; Complex; Intracellular; Environments

A unique trait shared by almost all living entities, apart from the capacity to reproduce, is the ability to transport material in a directed, regulated and timely fashion. Cells actively transport cargo in membrane enclosed sacs between different regions of the cell and to the cellular periphery and back. This is accomplished in large part by teams of molecular motors that can attach to the cargo and use chemical energy to power mechanical motion along a road network that is an assembly of protein filaments called the cytoskeleton. Remarkably, while intracellular transport is typically robust, it occurs in an extremely hostile environment where cargo undergo constant collisions from surrounding molecules and the cytoskeletal networks continually change in time. This project will produce a comprehensive mathematical model of intracellular transport that integrates features at the level of single molecular motors, teams of motors and also at the level of the cytoskeleton which spans the cell. This model will provide understanding of how cells maintain robust transport in highly noisy environments and will also help ascertain how the parameters governing transport can be tuned for minimizing variability and promoting efficient transport. Since intracellular transport is essential for cellular function and its breakdown can lead to multiple neurodegenerative and cardiac diseases, results from this project can potentially inform the optimal design of drug and gene delivery systems as well as therapeutic interventions to repair transport. This project will also produce new teaching and training materials and aid in their dissemination to the local community colleges in the historically underserved and economically disadvantaged California Central Valley region. This project is also aimed at providing training opportunities for graduate and undergraduate students, including women and underrepresented minorities.At the cellular scale, motion is governed by molecular-level events and is inherently stochastic. In addition, the environment in which the transport takes place is typically structurally complex as well as dynamic, either due to thermal noise or via regulation by the cell itself. Intracellular transport of cargo between different cell organelles and to the surface and back, occurs by a combination of diffusion and active motor-driven transport along the cytoskeleton which is a hierarchically assembled, oriented, interconnected network of multiple filament types that are inherently dynamic. While there has been considerable work addressing the mechanistic details of molecular motors, much less is known about actual transport properties in naturally occurring complex and dynamic settings. Current approaches to transport at a large scale usually sweep molecular details into effective parameters though it is becoming clear that collective transport can sensitively depend on these details. Furthermore, in virtually all cases, the explicit structure and dynamics of the cytoskeletal network is ignored. This project takes a multi-scale approach that incorporates the various microscopic processes at the level of a single motor, the mesoscopic properties of collections of motors and the macroscopic features of the cytoskeletal network which all conspire to give rise to robust transport. This work will provide fundamental insight into the role of microscopic stochastic motion and environmental dynamics on experimental observations of in vivo transport. The project results will also help with ascertaining what regions of parameter/design space are best for minimizing variability and promoting efficient transport. This project's results are therefore likely to have a significant impact on the optimal design and control of transport processes for general application in therapeutics and biotechnology.

除了繁殖能力之外，几乎所有生物都具有一个独特的特征，那就是能够以一种有方向、有规律和及时的方式运输物质。细胞在细胞的不同区域之间的膜封闭囊中主动运输货物，并运输到细胞周边和背面。这在很大程度上是由一组分子马达完成的，这些马达可以附着在货物上，并利用化学能为机械运动提供动力，使其沿着一个道路网络运动，该道路网络是一种称为细胞骨架的蛋白质细丝的集合体。值得注意的是，虽然细胞内转运通常是稳健的，但它发生在极其恶劣的环境中，其中货物经历与周围分子的不断碰撞，并且细胞骨架网络随时间不断变化。该项目将产生一个全面的细胞内运输的数学模型，该模型集成了单个分子马达水平，马达组水平以及跨越细胞的细胞骨架水平的特征。 该模型将提供细胞如何在高噪声环境中保持稳健的运输的理解，也将有助于确定如何调整管理运输的参数，以最大限度地减少变异性和促进有效的运输。由于细胞内转运对细胞功能至关重要，其破坏可能导致多种神经退行性疾病和心脏疾病，因此该项目的结果可能会为药物和基因递送系统的最佳设计以及修复转运的治疗干预提供信息。该项目还将编制新的教学和培训材料，并协助向历来服务不足和经济落后的加州中央谷地区的地方社区学院传播这些材料。该项目还旨在为研究生和本科生，包括妇女和代表性不足的少数群体提供培训机会，在细胞尺度上，运动受分子水平事件的支配，具有内在的随机性。此外，运输发生的环境通常是结构复杂的，以及动态的，由于热噪声或通过细胞本身的调节。货物在不同细胞器之间的细胞内运输以及到表面和背面，通过扩散和沿着细胞骨架沿着的主动马达驱动的运输的组合发生，所述细胞骨架是固有动态的多个细丝类型的分级组装、定向、互连网络。虽然已经有相当多的工作解决分子马达的机械细节，少得多的是已知的实际运输性质在自然发生的复杂和动态设置。 目前的方法，在大规模的运输通常扫描分子的细节到有效的参数，虽然它是越来越清楚，集体运输可以敏感地依赖于这些细节。此外，在几乎所有的情况下，明确的结构和动态的细胞骨架网络被忽略。该项目采用多尺度方法，在单个电机水平上结合了各种微观过程，电机集合的介观特性和细胞骨架网络的宏观特征，这些都有助于产生强大的运输。 这项工作将提供基本的洞察微观随机运动和环境动力学在体内运输的实验观察的作用。项目结果还将有助于确定哪些参数/设计空间区域最适合最大限度地减少可变性和促进高效运输。因此，该项目的结果很可能对治疗学和生物技术中一般应用的运输过程的优化设计和控制产生重大影响。