Modeling Transport in Complex Intracellular Environments

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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.