CAREER: Coordinating Diverse Physical Mechanisms for Intracellular Transport

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This research represents a fundamental study of the physics of intracellular transport, bringing new quantitative approaches to bear on the recent explosion of dynamic imaging data from living cells. By taking into account features unique to the intracellular environment, this work will make it possible to connect molecular-scale in vitro measurements of motor-cargo complexes with their behavior inside living cells. Furthermore, by analyzing in vivo imaging data in the context of quantitative transport models, the group will be able to identify the contributions of different transport modalities and pinpoint the key factors that control the balance between them. The development of predictive models for the effect of physical parameters on cell-scale transport is crucial to understanding how cells regulate organelle localization, to unraveling the mechanisms and biological consequences of transport defects, and to enabling experimental control of intracellular organization. The project is integrated with a complementary educational program that will provide opportunities for a diverse group of students (ranging from K-12 to graduate students) to explore scientific inquiry at the interface between physics and biology. Outreach efforts include the development of hands-on exploratory activities implemented in a "Young Scientists' Club" through partnership with a local elementary school and a module of the Tech Trek summer camp for middle school girls. These outreach efforts aim to broaden young students' conception of what a scientist does, while providing an early introduction to key practices of scientific research and basic concepts in the physical sciences. Research opportunities in the PI's lab are provided each summer to high school and undergraduate students to experience first-hand the nature of theoretical research at the nexus between physics and biology. Additionally, the PI is involved in teaching a summer bootcamp course to provide life sciences graduate students selected from around the world with a strong foundation of quantitative modeling skills.Biological processes ranging from metabolism to cell signaling to endocytosis require efficient movement and sorting of organelles and molecular complexes through a dynamic yet structured intracellular environment. The major modes of transport for cytoplasmic particles include diffusion, motor-driven transport along cytoskeletal filaments, and advective flow of the cytoplasm itself. A wealth of in vivo data on intracellular dynamics has become available in recent years. However, the fundamental physical mechanisms dictating this motion and the extent to which a cell can control and harness cytoplasmic dynamics for biological function remain poorly understood. In this project the PI employs theoretical and computational approaches, coupled with analysis of live cell imaging data, to explore the multi-faceted physics of intracellular transport, focusing on (1) the interplay between different transport modes, (2) the mechanics of motor-driven transport, and (3) the role of hydrodynamics in the cytoplasm. This approach brings together new results in statistical physics and soft matter mechanics with imaging data generated by collaborating cell biology groups. The PI will develop analytical results backed by stochastic simulations for delineating how the parameters of multi-modal transport and the arrangement of microtubule tracks control the dispersion and localization of organelles throughout the cytoplasm. The general mathematical model will be tested against observed organelle trajectories in tubular cell projections, including the motion of peroxisomes in fungal hyphae and mitochondria in neuronal axons. A major focus of this work will be on the mechanical and hydrodynamic aspects of active transport in eukaryotic cells. Leveraging results from polymer physics, the group will develop a physical model for transport in the presence of obstacles and through permeating cytoskeletal networks. The PI will also explore the mechanics of hitchhiking, a newly discovered form of directed transport. By bringing together approaches from soft matter physics with coarse-grained simulation techniques and data on the motion of key cytoplasmic components, this work will shed new light on the mechanisms by which cells control the distribution and delivery of their organelles.This project is being jointly supported by the Physics of Living Systems program in the Division of Physics and the Cellular Dynammics and Function Cluster in the Division of Molecular and Cellular Biosciences.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.