Modeling and analysis of actin filament organization in yeast

描述（由申请人提供）：几乎所有真核细胞都使用肌动蛋白进行多种生命过程。细胞在肌动蛋白丝的帮助下移动、分裂、组织内部，并建立和保持其形状。重复的，相同的亚基在不同的细胞类型中相似，构成了这些细丝。尽管这些纤维具有共同的性质，但细胞利用一系列蛋白质来完成各种各样的任务，如成核、帽状、切断、分支、交联以及沿它们沿着移动。这项工作的目的是（i）了解细胞如何利用肌动蛋白完成特定任务，以及（ii）将我们对肌动蛋白系统的理解推向预测数学模型所表达的物理图像。本研究以裂殖酵母为真核细胞模型。该方法结合了数学建模，图像分析和实验生物学来研究细胞如何组织肌动蛋白。两个假设构成了研究的基础。首先，交联蛋白质有助于在分裂的最后一步形成一个环，将细胞质分开。第二，成核蛋白和切断蛋白与约束一致，将肌动蛋白组织成电缆。该研究建议通过以下方式来测试这些假设：（i）从这些结构的显微镜图像中提取相关量，（ii）建立这些结构的数学模型，强调可测量的量，以及（iii）与实验学家合作，使这些模型受到严格的挑战。图像分析使用了新的工具，例如与计算机科学家合作开发的自动化细丝和顺应网络跟踪工具。数学建模利用离散和连续的方法相结合的动态系统的实验参数。实验挑战是与吴建秋实验室合作进行的，形式包括遗传操作、药物治疗和荧光显微镜。这项研究的每个方面都导致了对肌动蛋白细胞骨架及其作用的机械理解，这将基于对细胞功能的深入理解来支持未来的癌症和健康研究。

DESCRIPTION (provided by applicant): Almost all eukaryotic cells use actins for multiple vital processes. Cells move, divide, organize their interior, and establish and maintain their shape with the help of actins filaments. Repeated, identical subunits similar across cell types make up these filaments. Despite the common nature of the filaments, cells co-opt them for multifarious tasks with a spectrum of proteins to nucleate, cap, sever, branch, cross-link, and move along them. This work aims both (i) to understand how cells employ actins for specific tasks and (ii) to push our understanding of the actins system towards a physical picture expressed by predictive mathematical models. This study focuses on fission yeast as a model eukaryotic cell. The proposed approach combines mathematical modeling, image analysis, and experimental biology to study how cells organize actins. Two hypotheses form the basis of the study. First, that cross-linking proteins aid the formation of a ring that divides the cytoplasm during the final step of division. Second, that nucleating proteins and severing proteins act in concert with confinement to organize actins into cables. The study proposes to test these hypotheses by (i) extracting relevant quantities from micro- scope images of these structures, (ii) building mathematical models of these structures emphasizing measurable quantities, and (iii) collaborating with experimentalists to subject these models to rigorous challenges. The image analysis uses novel tools, such as tools for automated filament and filament-network tracking, developed in collaboration with computer scientists. The mathematical modeling makes use of a combination of discrete and continuum approaches to dynamical systems informed by experimental parameters. The experimental chal- lenges come in collaboration with Jian-Qiu Wu's lab and in the form of genetic manipulations, pharmacological treatments, and fluorescence microscopy. Every aspect of the study leads to a mechanistic understanding of the actins cytoskeleton and its roles that would underpin future cancer and health research based on an advanced understanding of cellular function.