CAREER: Coordinating Diverse Physical Mechanisms for Intracellular Transport

这项研究代表了对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性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，这项工作将使在分子尺度上对马达-货物复合体的体外测量与它们在活细胞内的行为联系起来。此外，通过在定量运输模型的背景下分析活体成像数据，该小组将能够识别不同运输方式的贡献，并准确地确定控制它们之间平衡的关键因素。建立物理参数对细胞尺度运输影响的预测模型，对于理解细胞如何调节细胞器定位，揭开运输缺陷的机制和生物学后果，以及实现对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，将为不同的学生群体(从K-12到研究生)提供机会，在物理和生物之间的界面上探索科学探究。外联工作包括通过与当地一所小学的伙伴关系在“青年科学家俱乐部”开展实践探索活动，以及为中学女孩举办的科技之旅夏令营的一个单元。这些外展工作旨在扩大年轻学生对科学家工作的认识，同时及早介绍科学研究的关键实践和物理科学的基本概念。每年夏天，国际物理研究所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的理论研究的本质。此外，PI还参与了夏季训练营课程的教学，为从世界各地挑选的生命科学研究生提供坚实的定量建模技能基础。从新陈代谢到细胞信号再到内吞作用的生物过程需要细胞器和分子复合体在动态而结构化的细胞内环境中有效地移动和分选。细胞质颗粒的主要运输方式包括扩散、马达驱动的沿细胞骨架细丝的运输以及细胞质本身的平流流。近年来，关于细胞内动力学的大量体内数据已经成为可能。然而，决定这一运动的基本物理机制以及细胞可以控制和利用细胞质动力学以实现生物功能的程度仍然知之甚少。在这个项目中，PI使用理论和计算方法，结合对活细胞成像数据的分析，探索细胞内运输的多方面物理，重点是(1)不同运输方式之间的相互作用，(2)电机驱动的运输机制，以及(3)细胞质中流体动力学的作用。这种方法将统计物理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，以描绘多模式运输的参数和微管轨迹的排列如何控制细胞器在细胞质中的分散和定位。通用数学模型将根据观察到的管状细胞投射中的细胞器轨迹进行测试，包括真菌菌丝中的过氧化物体和神经元轴突中的线粒体的运动。这项工作的一个主要焦点将是真核细胞主动运输的机械和流体动力学方面。利用聚合物物理学的成果，该小组将开发一个物理模型，用于在存在障碍的情况下通过渗透的细胞骨架网络进行运输。PI还将探索搭便车的机制，这是一种新发现的定向交通形式。通过将软物质物理的方法与粗粒度模拟技术和关键细胞质组件运动的数据结合在一起，这项工作将揭示细胞控制其细胞器的分布和传递的机制。该项目由物理部的生命系统物理学计划和分子和细胞生物科学部的细胞动力学和功能簇共同支持。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势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.