CAREER: Multiscale investigations of micromechanics of cytoskeletal protofilaments

研究：细胞在与其他细胞或其环境相互作用过程中施加的张力会导致细胞变形，并导致蛋白质合成和膜特性的变化。细胞中的细丝，如肌动蛋白和微管，通过其机械性能和与细胞辅助因子的广泛通信来介导力的作用。在细胞迁移过程中，细胞骨架细丝在外力作用下需要快速重组，这对发育和组织修复与再生是重要的。此外，主要为了产生力量而存在的肌肉细胞都使用由肌动蛋白细丝和细胞辅助因子(肌球蛋白)组成的分子马达来产生活跃的收缩。微管负责控制染色体和细胞内其他细胞器的定向运动，这对正确的细胞分裂是必不可少的。在分子水平上理解细胞骨架细丝介导力传递的复杂机制以及每种类型的细丝对细胞结构稳定性的贡献仍然是现代生物学面临的挑战。本研究的目的是阐明力对细丝内部组织的影响及其与细丝大尺度力学行为的联系。将采用三种类型的计算研究：(1)确定力模式和由此导致的表征细胞骨架原丝对力的响应的构象变化；(2)阐明由细胞因素切断细丝所涉及的力-结构关系；(3)表征在张力存在下，链间键的拓扑和化学对细丝聚合和解聚动力学的贡献。这些研究的结果将与大量关于原丝的实验数据进行比较和对比。在这个项目中获得的新知识将有助于为未来对辅助因素的身份和作用机制的研究提供概念性指导，这些辅助因素在建立细胞的力学和化学之间的联系方面具有关键作用。广泛影响：DIMA教授的长期职业目标是在指导、教学和研究之间创建协同，从而培训未来的科学劳动力。研究和教育的整合将在这个项目中通过多尺度计算方法的本科生和研究生的教学和指导来完成，以研究大型细胞系统。这些活动，再加上旨在尽早向来自代表人数不足的少数民族的中学女孩介绍科学调查的外联举措，将为下一代多样化和受过广泛培训的劳动力做好准备。DIMA教授在这个项目中的工作将通过实施合作学习和将研究主题纳入课堂来提高本科生对物理化学的理解，从而加强辛辛那提大学的教育基础设施。

Research: Tension applied to cells during their interaction with other cells or with their environment leads to their deformation and induces changes in protein synthesis and membrane properties. Filaments in the cell such as actin and microtubules mediate the action of force through their mechanical properties and their extensive communications with cellular co-factors. Fast reorganization of cytoskeletal filaments under applied forces is required during cell migration, which is important for development and tissue repair and regeneration. Moreover, muscle cells that exist primarily to generate force all use the molecular motor comprised of actin filaments and a cellular co-factor (myosin) to produce active contraction. Microtubules are responsible for the controlled directional movement of chromosomes and other organelles within the cell, which is essential for correct cell division. Understanding, at the molecular level, the complex mechanisms whereby cytoskeletal filaments mediate force transmission and the contribution of each type of filament to the structural stability of the cell is still a challenge for modern biology. The goal of this research is to elucidate the effect of forces on the internal organization of the filaments and its connection with the large-scale mechanical behavior of filaments. Computational studies of three types will be employed (1) determination of force regimes and the resulting conformational changes that characterize the response of cytoskeletal protofilaments to force; (2) elucidation of the force-structure relationships involved in the severing of filaments by cellular factors;(3) characterization of the contributions of the topology and the chemistry of inter-chain bonds to the kinetics of polymerization and depolymerization of filaments in the presence of tension. The results of these investigations will be compared and contrasted to a wealth of experimental data on protofilaments. The new knowledge gained in this project will help provide conceptual guidance for future investigations into the identity and mechanisms of action of co-factors with crucial roles in establishing the connection between the mechanics and the chemistry of the cell.Broader impacts: Prof. Dima's long-term career goal is to create a synergy between mentoring, teaching, and research leading to the training of the future scientific workforce. The integration of research and education will be accomplished in this project through the teaching and mentoring of undergraduate and graduate students in multiscale computational approaches to investigate large cellular systems. These activities, coupled with outreach initiatives aimed at the early introduction of scientific inquiry to middle school girls from underrepresented minorities, will prepare the next generation of diverse and broadly trained workforce. Prof. Dima's work in this project will enhance the educational infrastructure at the University of Cincinnati by improving undergraduate students' understanding of Physical Chemistry through implementing cooperative learning and incorporating research topics into lectures.