Theory of dynamic cytoskeletal length regulation and stabilization

该奖项支持理论和计算研究，以及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，它们调节它们达到的大小：例如，人长到成年人的高度，然后保持这个高度。因此，感知和调节尺寸是生物有机体解决的一个基本物理问题。生命系统不仅控制整个生物体的大小，还控制更小的内部结构（器官，细胞和细胞内的结构）。生物学中感知和控制大小的物理原理和机制还没有得到很好的理解。该项目将开发新的基于物理学的模型，以了解和预测生物体中一类亚细胞结构的长度是如何调节的。相关的机制可能在调节聚合物和生物材料的生长方面是有用的。 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。技术概述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未得到很好的理解。聚合物长度的调节对于细胞骨架的组织是重要的，其影响亚细胞器如有丝分裂纺锤体的大小和细胞自身的结构。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，许多细胞骨架组装体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。虽然以前的重要工作集中在稳态主轴长度，PI的目的是提高动态主轴长度调节的理解。从这项工作的结果将提供一个基础，发展预测了解动态长度调节和细胞骨架自组装。这项工作是建立在理论和建模工具，包括易处理的分析模型，半解析和数值分析，简化的仿真模型，并详细的三维模拟。这个项目将解决如何长度调节和它的动态稳定可以出现作为一个集体财产的水平从单丝，丝束，和有丝分裂纺锤体的细胞骨架组装的变化。这项工作将集中在两个科学问题上。首先，单细胞骨架丝、束和高阶组装体的长度感知的一般机制是什么？虽然以前的长度感测工作已经假设单调长度依赖的过程，这项工作将进行广泛的理论研究到类的长度感测，目前已知的生物过程的启发。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？最近的工作表明，有丝分裂纺锤体的长度是动态稳定在一个稳定的状态值，这种稳定可以被扰动，造成大的长度波动。这项工作将进行反馈和放大，导致动态稳定或不稳定的长度的细胞骨架组件类的一般调查。研究中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性调节如何影响长度感知，从而深入了解生物学相关的长度感知和调节的一般机制。这项工作将发展动态稳定的理解，并调查是否有不同的特征模式的动态失稳。研究进展可能适用于生物材料和软材料的生长。该项目还将通过考虑主轴部件如何提供力和反馈来测试主轴长度稳定的机械贡献，从而实现恒定，稳定的主轴长度。这将提高对细胞中集体自组装的理解。该项目是理论生物物理学和统计力学的综合跨学科计划，由细胞生物学和遗传学提供信息，以深入了解细胞骨架长度调节和稳定。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NSF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。

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.