Modeling Transport in Complex Intracellular Environments

除繁殖能力外，几乎所有生命实体都有一个独特的特点，那就是能够以定向、规范和及时的方式运输材料。细胞主动地在细胞不同区域之间的膜封闭的囊中运输货物，并将其运往细胞的外围和背面。这在很大程度上是由分子马达团队完成的，分子马达可以附着在货物上，并使用化学能推动沿道路网络的机械运动，该网络是蛋白质细丝的组装，称为细胞骨架。值得注意的是，虽然细胞内的运输通常是强大的，但它发生在极其恶劣的环境中，货物不断受到周围分子的碰撞，细胞骨架网络不断随着时间的变化而变化。该项目将产生一个全面的细胞内运输数学模型，该模型集成了单分子马达、马达团队以及跨越细胞的细胞骨架水平的特征。这一模型将有助于理解细胞如何在高噪音环境中保持稳健的传输，并将有助于确定如何调整管理传输的参数，以最大限度地减少变异性和促进高效传输。由于细胞内转运对细胞功能至关重要，其崩溃可能导致多种神经退行性疾病和心脏疾病，该项目的结果可能会为药物和基因输送系统的最佳设计以及修复运输的治疗干预提供信息。该项目还将制作新的教学和培训材料，并帮助将其传播给加州中央山谷地区历史上服务不足和经济困难的当地社区大学。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民族提供培训机会。在细胞尺度上，运动由分子水平的事件控制，本质上是随机的。此外，由于热噪声或通过细胞本身的调节，发生运输的环境通常在结构上复杂且动态。不同细胞细胞器之间的细胞内运输以及到表面和背面的运输，是通过沿细胞骨架的扩散和主动马达驱动的运输相结合的方式发生的，细胞骨架是由内在动态的多种细丝类型组成的分级组装的、定向的、相互连接的网络。虽然已经有相当多的工作解决了分子马达的机械细节，但关于自然发生的复杂和动态环境中的实际传输性质的了解要少得多。目前大规模运输的方法通常将分子细节扫描成有效的参数，尽管越来越明显的是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，细胞骨架网络的明确结构和动力学都被忽略了。该项目采用多尺度方法，结合了单一马达层面的各种微观过程、马达集合的介观性质和细胞骨架网络的宏观特征，所有这些都有助于产生强大的运输能力。这项工作将为微观随机运动和环境动力学在体内运输实验观察中的作用提供基本的见解。项目成果还将有助于确定参数/设计空间的哪些区域最适合最大限度地减少变异性和促进高效运输。因此，该项目的结果可能对治疗学和生物技术中普遍应用的运输过程的优化设计和控制产生重大影响。

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.