Modeling and analysis of actin filament organization in yeast

酵母肌动蛋白丝组织的建模和分析

基本信息

批准号：
8601889
负责人：
Dimitrios Vavylonis
金额：
$ 27.16万
依托单位：
LEHIGH UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-03-23 至 2016-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8601889
关键词：
ATP Hydrolysis Actins Animal Model Basic Science Binding Proteins Biological Biological Process Biology Bundling Cell Cycle Cell Shape Cell division Cell physiology Cells Characteristics Collaborations Complex Computer Simulation Computers Cytokinesis Cytoplasm Cytoskeleton Diffuse Diffusion Elements Eukaryotic Cell Filament Fission Yeast Fluorescence Microscopy Future Geometry Goals Growth Health Hour Human Image Image Analysis Indium Length Malignant Neoplasms Measurable Mechanical Stress Medial Mediating Methods Microfilaments Microscope Modeling Molecular Morphology Motor Myosin ATPase Nature Pharmacological Treatment Physical condensation Process Proteins Research Role Scientist Shapes Side Skeleton Spatial Distribution Staging Structure System Takeda brand of pioglitazone hydrochloride Testing Time Transport Vesicles Work Yeasts base cell growth cell type crosslink depolymerization design genetic manipulation link protein mathematical model nanometer novel physical process polymerization prevent research study tool

项目摘要

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.

描述（由申请人提供）：几乎所有真核细胞都使用肌动蛋白来进行多种生命过程。细胞在肌动蛋白丝的帮助下移动、分裂、组织其内部，并建立和维持其形状。这些细丝由不同细胞类型重复、相似的亚基组成。尽管细丝具有共同的性质，但细胞却利用它们来执行多种任务，使用一系列蛋白质来成核、封闭、切断、分支、交联并沿着它们移动。这项工作的目的是（i）了解细胞如何利用肌动蛋白来完成特定任务，以及（ii）将我们对肌动蛋白系统的理解推向由预测数学模型表达的物理图像。这项研究的重点是裂殖酵母作为模型真核细胞。所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，交联蛋白有助于形成一个环，在分裂的最后一步中将细胞质分开。其次，成核蛋白和切割蛋白与限制协同作用，将肌动蛋白组织成电缆。该研究建议通过以下方式测试这些假设：（i）从这些结构的显微图像中提取相关量，（ii）建立这些结构的数学模型，强调可测量的量，以及（iii）与实验人员合作，使这些模型面临严格的挑战。图像分析使用新颖的工具，例如与计算机科学家合作开发的自动灯丝和灯丝网络跟踪工具。数学建模结合了离散和连续方法，对由实验参数提供的动力系统进行建模。实验挑战来自与吴建秋实验室的合作，形式包括基因操作、药物治疗和荧光显微镜。该研究的各个方面都会导致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为未来的癌症和健康研究奠定基础。