CAREER: Coordinating Diverse Physical Mechanisms for Intracellular Transport

这项研究代表了细胞内运输物理学的基础研究，为最近来自活细胞的动态成像数据的爆炸式增长带来了新的定量方法。通过考虑细胞内环境的独特特征，这项工作将有可能将motor-cargo复合物的分子尺度体外测量与其在活细胞内的行为联系起来。此外，通过在定量转运模型的背景下分析体内成像数据，该小组将能够确定不同转运模式的贡献，并查明控制它们之间平衡的关键因素。物理参数对细胞尺度运输影响的预测模型的发展对于理解细胞如何调节细胞器定位，揭示运输缺陷的机制和生物学后果，以及实现细胞内组织的实验控制至关重要。该项目与一个互补的教育项目相结合，将为不同群体的学生（从K-12到研究生）提供机会，探索物理学和生物学之间的科学探究。外联工作包括通过与当地一所小学合作，在“青年科学家俱乐部”开展实践探索活动，并为中学女生提供Tech Trek夏令营的一个模块。这些拓展工作旨在拓宽年轻学生对科学家工作的概念，同时提供对科学研究的关键实践和物理科学基本概念的早期介绍。每年夏天，PI的实验室都会为高中生和本科生提供研究机会，让他们亲身体验物理学和生物学之间联系的理论研究的本质。此外，PI还参与教授夏季训练营课程，为从世界各地挑选的生命科学研究生提供定量建模技能的坚实基础。从代谢到细胞信号传导到内吞作用的生物过程需要细胞器和分子复合物在动态而结构化的细胞内环境中进行有效的运动和分类。细胞质颗粒的主要运输方式包括扩散、沿细胞骨架细丝的马达驱动运输和细胞质本身的平流。近年来，关于细胞内动力学的大量体内数据已经变得可用。然而，决定这种运动的基本物理机制以及细胞能够控制和利用细胞质动力学来实现生物功能的程度仍然知之甚少。在这个项目中，PI采用理论和计算方法，结合活细胞成像数据的分析，探索细胞内运输的多方面物理，重点关注(1)不同运输模式之间的相互作用，(2)马达驱动运输的力学，以及(3)流体力学在细胞质中的作用。这种方法将统计物理学和软物质力学的新结果与合作细胞生物学小组产生的成像数据结合在一起。PI将开发由随机模拟支持的分析结果，以描述多式联运的参数和微管轨道的排列如何控制细胞器在细胞质中的分散和定位。一般的数学模型将根据观察到的管状细胞突起的细胞器轨迹进行测试，包括真菌菌丝中的过氧化物酶体和神经元轴突中的线粒体的运动。这项工作的主要重点将放在真核细胞主动转运的机械和流体动力学方面。利用聚合物物理学的结果，该小组将开发一个在障碍物存在下通过渗透细胞骨架网络进行运输的物理模型。PI还将探索搭便车的机制，这是一种新发现的定向运输形式。通过将软物质物理学的方法与粗粒度模拟技术和关键细胞质组分运动的数据结合起来，这项工作将为细胞控制其细胞器分布和传递的机制提供新的线索。该项目由物理系的生命系统物理学项目和分子与细胞生物科学系的细胞动力学和功能集群共同支持。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

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.