CAREER: Multiscale investigations of micromechanics of cytoskeletal protofilaments

职业：细胞骨架原丝微观力学的多尺度研究

• 批准号: 0845002
• 负责人: Ruxandra Dima
• 金额: $ 61.15万
• 依托单位: University of Cincinnati Main Campus
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-03-01 至 2015-02-28
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=0845002&HistoricalAwards=false
• 关键词: CAREER; Multiscale; investigations; micromechanics; cytoskeletal

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.

研究：在细胞与其他细胞或其环境相互作用期间施加于细胞的张力导致其变形并诱导蛋白质合成和膜特性的变化。细胞中的纤维，如肌动蛋白和微管，通过它们的机械特性和它们与细胞辅因子的广泛通讯来介导力的作用。在细胞迁移过程中，细胞骨架丝在外力作用下的快速重组是必需的，这对发育和组织修复与再生非常重要。此外，主要产生力量的肌肉细胞都使用由肌动蛋白丝和细胞辅因子（肌球蛋白）组成的分子马达来产生主动收缩。微管负责细胞内染色体和其他细胞器的受控定向运动，这对正确的细胞分裂至关重要。在分子水平上理解细胞骨架丝介导力传递的复杂机制以及每种类型的丝对细胞结构稳定性的贡献仍然是现代生物学的挑战。本研究的目的是阐明力对纤维内部组织的影响及其与纤维大尺度力学行为的联系。计算研究将采用三种类型：（1）确定力的制度和由此产生的构象变化，表征细胞骨架原丝对力的反应;（2）阐明力与结构的关系，涉及切断丝细胞因子;（3）表征了分子间的拓扑结构和化学性质的贡献，链键与张力存在下长丝的聚合和解聚动力学有关。这些调查的结果将进行比较，并与大量的实验数据的原丝。在这个项目中获得的新知识将有助于为未来的研究提供概念指导，以确定在建立细胞力学和化学之间的联系中起关键作用的辅助因子的身份和作用机制。更广泛的影响：Dima教授的长期职业目标是在指导，教学和研究之间创造协同效应，从而培养未来的科学工作者。研究和教育的整合将在这个项目中完成，通过教学和指导本科生和研究生在多尺度计算方法来调查大型细胞系统。这些活动，加上旨在尽早向代表性不足的少数群体的中学女生介绍科学探究的外联举措，将为下一代多样化和受过广泛培训的劳动力做好准备。迪马教授在该项目中的工作将通过实施合作学习和将研究课题纳入讲座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。