Theory of dynamic cytoskeletal length regulation and stabilization

非技术总结该奖项支持理论和计算研究，以及关于决定活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，人长到成年时的高度，然后保持那么高。因此，感知和调节大小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有机体的大小，而且控制更小的内部结构(器官、细胞和细胞内结构)的大小。生物学中感知和控制大小的物理原理和机制还没有被很好地理解。该项目将开发新的基于物理的模型，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。相关的机制可能有助于调节聚合物和生物材料的生长。这个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。技术总结该奖项支持理论和计算研究，以及关于决定活生物体和仿生生物材料大小的基本机制的教育。调节身体大小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大小的物理原理和机制尚未被很好地理解。聚合物长度的调节对细胞骨架的组织很重要，它影响亚细胞细胞器的大小，如有丝分裂纺锤体和细胞本身的结构。一个重要的一般性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。虽然之前的大量工作都集中在稳态主轴长度上，但PI的目的是促进对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、半解析和数值分析、简化的模拟模型和详细的三维模拟。这个项目将解决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，长度调节及其动态稳定性作为集体属性出现。这项工作将集中在两个科学问题上。首先，单细胞骨架细丝、束和更高阶组件的长度传感的一般机制是什么？虽然以前的长度传感工作假定长度依赖于单调的过程，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？最近的工作表明，有丝分裂纺锤体的长度动态地稳定在一个稳定值，并且这种稳定可以被干扰，导致很大的长度波动。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类别进行一般调查。这项研究探索的机制可能适用于调控聚合物和生物材料的生长。这项工作将通过确定捆绑、空间非单调活性和力相关调控如何影响长度传感，为深入了解与生物相关的长度传感和调控的一般机制提供洞察。这项工作将加深对动力稳定的理解，并调查是否存在不同的动力失稳特征模式。更广泛地说，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组件如何提供力和反馈来实现恒定、稳定的主轴长度，来测试机械对主轴长度稳定的贡献。这将提高对细胞中集体自组装的理解。该项目是一个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的调节和稳定。PI致力于通过多项活动增加科学领域的性别和种族多样性。这一奖项反映了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。

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.