Theory of dynamic cytoskeletal length regulation and stabilization

动态细胞骨架长度调节和稳定理论

• 批准号: 1725065
• 负责人: Meredith Betterton
• 金额: $ 34.2万
• 依托单位: University of Colorado at Boulder
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-06-15 至 2022-05-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1725065&HistoricalAwards=false
• 关键词: Theory; dynamic; cytoskeletal; length; regulation

NONTECHNICAL SUMMARYThis award supports theoretical and computational research, and education on the fundamental mechanisms that determine size of living organisms and biomaterials. When biological organisms grow, they regulate the size that they reach: for example, people grow to their adult height and then remain that tall. Therefore, sensing and regulating size is an essential physics problem that biological organisms solve. Living systems control the size not just of whole organisms, but also of smaller internal structures (organs, cells, and structures inside cells). The physical principles and mechanisms underlying the sensing and control of size in biology are not well understood. This project will develop new physics-based models to understand and predict how length of one class of subcellular structures are regulated in organisms. Related mechanisms may be useful in regulating the growth of polymers and biomaterials. This project will develop interdisciplinary research and education, and work to improve diversity in science.TECHNICAL SUMMARYThis award supports theoretical and computational research, and education on the fundamental mechanisms that determine size of living organisms and biomimetic biomaterials. Regulating physical size is an essential problem that biological organisms must solve, but the physical principles and mechanisms underlying the sensing and control of size in biology are not well understood. The regulation of polymer length is important for the organization of the cellular cytoskeleton, which affects the size of subcellular organelles such as the mitotic spindle and the structure of cells themselves. An important general question is how to use molecular-level information to understand and predict higher-order aspects of assembly and organization. Remarkably, many cytoskeletal assemblies can maintain a constant, self-organized length, even though they are nonequilibrium structures with constant molecular turnover. While significant previous work has focused on steady-state spindle length, the PI aims to advance understanding of dynamic spindle length regulation. Results from this work will provide a basis for developing predictive understanding of dynamic length regulation and cytoskeletal self-assembly. The work is built on theoretical and modeling tools, including tractable analytic models, semi-analytic and numerical analysis, simplified simulation models, and detailed three-dimensional simulations. This project will address how length regulation and its dynamic stabilization can emerge as a collective property as the level of cytoskeletal assembly changes from single filaments, filament bundles, and the mitotic spindle. The work will focus on two scientific questions. First, what are the general mechanisms of length sensing of single cytoskeletal filaments, bundles, and higher-order assemblies? While previous length-sensing work has assumed monotonically length-dependent processes, this work will conduct a wide-ranging theoretical investigation into classes of length sensing, inspired by currently known biological processes. Second, what types of feedback and amplification lead to dynamically stable or unstable length regulation? Recent work demonstrates that mitotic spindle length is dynamically stabilized at a steady state value, and that this stabilization can be perturbed, causing large length fluctuations. The work will perform a general investigation of classes of feedback and amplification that lead to dynamically stable or unstable length of cytoskeletal assemblies. Mechanisms explored in the research may be applicable to regulating the growth of polymers and biomaterials.The work will provide insight into biologically relevant general mechanisms of length sensing and regulation, by determining how bundling, spatially non-monotonic activity, and force-dependent regulation can effect length sensing. The work will develop understanding of the dynamic stabilization, and investigate whether there are different characteristic modes of dynamic destabilization. Research advances may have applicability to growth of biomaterials and soft materials more generally. This project will also test mechanical contributions to spindle length stabilization, by considering how spindle components contribute forces and feedback that enable constant, stable spindle length. This will improve understanding of collective self-assembly in cells. The project is an integrated interdisciplinary program of theoretical biophysics and statistical mechanics informed by cell biology and genetics to gain insight into cytoskeletal length regulation and stabilization. The PI works to increase gender and racial diversity in science through multiple activities.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.

该奖项支持理论和计算研究，以及关于决定生物体和生物材料大小的基本机制的教育。当生物有机体生长时，它们会调节它们达到的大小：例如，人们长到成人的高度，然后保持那个高度。因此，感知和调节大小是生物有机体所要解决的一个重要物理问题。生命系统不仅控制整个生物体的大小，还控制较小的内部结构（器官、细胞和细胞内的结构）的大小。生物学中大小感知和控制的物理原理和机制尚不清楚。该项目将开发新的基于物理的模型，以了解和预测一类亚细胞结构的长度在生物体中是如何被调节的。相关机制可能有助于调节聚合物和生物材料的生长。该项目将发展跨学科的研究和教育，并致力于提高科学的多样性。该奖项支持理论和计算研究，以及决定生物体和仿生生物材料大小的基本机制的教育。调节物理尺寸是生物有机体必须解决的一个基本问题，但生物学中感知和控制尺寸的物理原理和机制尚不清楚。聚合物长度的调节对于细胞骨架的组织是重要的，它影响着亚细胞器的大小，如有丝分裂纺锤体和细胞本身的结构。一个重要的普遍问题是如何使用分子水平的信息来理解和预测组装和组织的高阶方面。值得注意的是，许多细胞骨架组件可以保持恒定的自组织长度，即使它们是具有恒定分子周转的非平衡结构。而显著以前的工作集中在稳态主轴长度，PI旨在推进动态主轴长度调节的理解。这项工作的结果将为发展对动态长度调节和细胞骨架自组装的预测性理解提供基础。这项工作建立在理论和建模工具的基础上，包括易于处理的分析模型、半分析和数值分析、简化的模拟模型和详细的三维模拟。该项目将研究长度调控及其动态稳定性如何在细胞骨架组装水平从单丝、丝束和有丝分裂纺锤体变化时作为一种集体属性出现。这项工作将集中在两个科学问题上。首先，单个细胞骨架细丝、束和高阶装配的长度感知的一般机制是什么？虽然以前的长度传感工作已经假设了单调的长度依赖过程，但这项工作将在目前已知的生物过程的启发下，对长度传感的类别进行广泛的理论研究。第二，什么类型的反馈和放大导致动态稳定或不稳定的长度调节？最近的研究表明，有丝分裂纺锤体长度是动态稳定在一个稳态值，这种稳定可以被扰乱，造成大的长度波动。这项工作将对导致细胞骨架组件动态稳定或不稳定长度的反馈和放大进行一般调查。所探索的机制可能适用于调节聚合物和生物材料的生长。这项工作将通过确定捆绑、空间非单调活动和力依赖调节如何影响长度感知，为生物相关的长度感知和调节的一般机制提供见解。这项工作将发展对动力稳定的理解，并研究是否存在不同的动力失稳特征模式。研究进展可能更广泛地适用于生物材料和软材料的生长。该项目还将测试机械对主轴长度稳定的贡献，通过考虑主轴组件如何贡献力和反馈，使主轴长度保持恒定、稳定。这将提高对细胞集体自组装的理解。该项目是一个综合跨学科的理论生物物理学和统计力学项目，以细胞生物学和遗传学为基础，深入了解细胞骨架长度的调节和稳定。PI致力于通过多种活动增加科学领域的性别和种族多样性。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。

项目成果

Collective motion of driven semiflexible filaments tuned by soft repulsion and stiffness

• DOI: 10.1039/d0sm01036g
• 发表时间: 2020-11-07
• 期刊: SOFT MATTER
• 影响因子: 3.4
• 作者: Moore, Jeffrey M.;Thompson, Tyler N.;Betterton, Meredith D.
• 通讯作者: Betterton, Meredith D.

Theory of Cytoskeletal Reorganization during Cross-Linker-Mediated Mitotic Spindle Assembly

• DOI: 10.1016/j.bpj.2019.03.013
• 发表时间: 2019-05-07
• 期刊: BIOPHYSICAL JOURNAL
• 影响因子: 3.4
• 作者: Lamson, Adam R.;Edelmaier, Christopher J.;Betterton, Meredith D.
• 通讯作者: Betterton, Meredith D.

Toward Task Capable Active Matter: Learning to Avoid Clogging in Confined Collectives via Collisions

迈向具有任务能力的活性物质：学习避免通过碰撞在有限的集体中发生堵塞

• DOI: 10.3389/fphy.2022.735667
• 发表时间: 2022
• 期刊: Frontiers in Physics
• 影响因子: 3.1
• 作者: Aina, Kehinde O.;Avinery, Ram;Kuan, Hui-Shun;Betterton, Meredith D.;Goodisman, Michael A.;Goldman, Daniel I.
• 通讯作者: Goldman, Daniel I.

Chiral self-sorting of active semiflexible filaments with intrinsic curvature

具有固有曲率的活性半柔性细丝的手性自排序

• DOI: 10.1039/d0sm01163k
• 发表时间: 2021
• 期刊: Soft Matter
• 影响因子: 3.4
• 作者: Moore, Jeffrey M.;Glaser, Matthew A.;Betterton, Meredith D.
• 通讯作者: Betterton, Meredith D.

Mechanisms of Selective Transport through the Nuclear Pore Complex

通过核孔复合体的选择性运输机制

• DOI: 10.1016/j.bpj.2017.11.2375
• 发表时间: 2018
• 期刊: Biophysical Journal
• 影响因子: 3.4
• 作者: Maguire, Laura;Stefferson, Michael;Betterton, Meredith;Hough, Loren
• 通讯作者: Hough, Loren