Modeling and analysis of actin filament organization in yeast

描述(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。细胞在肌动蛋白细丝的帮助下移动、分裂、组织内部，并建立和保持它们的形状。这些细丝由不同细胞类型相似的相同亚基重复组成。尽管细丝具有共同的性质，但细胞利用它们来完成各种各样的任务，并使用一系列蛋白质来成核、覆盖、切断、分支、交叉连接，并沿着它们移动。这项工作的目的既是(I)了解细胞如何在特定任务中使用肌动蛋白，(Ii)将我们对肌动蛋白系统的理解推向由预测性数学模型表达的物理图景。本研究以裂解酵母作为真核细胞的模型。提出的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。两个假设构成了这项研究的基础。首先，这种交联蛋白有助于形成一个环，在分裂的最后一步分裂细胞质。第二，核蛋白和切断蛋白与限制作用协同作用，将肌动蛋白组织成电缆。这项研究建议通过(I)从这些结构的微观图像中提取相关的量，(Ii)建立这些结构的数学模型，强调可测量的量，以及(Iii)与实验者合作，使这些模型受到严格的挑战，来检验这些假设。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细丝和细丝网络跟踪工具。该数学模型利用离散和连续相结合的方法来处理受实验参数影响的动力系统。实验中的查尔长是与吴建秋的实验室合作，以遗传操作、药物治疗和荧光显微镜的形式进行的。这项研究的每一个方面都导致了对肌动蛋白、细胞骨架及其作用的机械性理解，这将在对细胞功能的高级理解的基础上，为未来的癌症和健康研究奠定基础。

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.