Modeling Contractile Ring Constriction in Fission Yeast

裂殖酵母的收缩环收缩建模

• 批准号: 8061671
• 负责人: Ben O'Shaughnessy
• 金额: $ 30.05万
• 依托单位: COLUMBIA UNIV NEW YORK MORNINGSIDE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8061671
• 关键词: Ablation; Actinin; Actins; Actomyosin; Address; Adopted; Animal Model; Animals; Biological Models; Cell Cycle; Cell Cycle Stage; Cell Wall; Cell division; Cells; Cellular Stress; Collaborations; Complication; Computer Simulation; Congenital Abnormality; Contractile System; Coupling; Cytokinesis; Cytoplasm; Defect; Deposition; Disease; Electrons; Event; Excision; Feedback; Figs - dietary; Fission Yeast; Generations; Gerbils; Goals; Growth; Kinetics; Lasers; Learning; Left; Life; Link; Malignant Neoplasms; Mammalian Cell; Measures; Membrane; Microfilaments; Modeling; Molecular; Mothers; Motor; Muscle; Myofibrils; Myosin ATPase; Outcome; Pathology; Phase; Process; Property; Proteins; Protoplasts; Quantitative Microscopy; Relaxation; Research; Research Project Grants; Shapes; Slide; Staining method; Stains; Stress; Stress Fibers; Structure; Swelling; System; Testing; Translating; Work; Wound Healing; Yeasts; base; cofilin; constriction; daughter cell; depolymerization; fibroma; fungus; mathematical model; nervous system disorder; polymerization; programs; public health relevance; research study; theories; therapy development; time use

DESCRIPTION (provided by applicant): Cytokinesis is the process ending the cell cycle in which the mother cell cytoplasm divides into two. As a critical step in cell division it is fundamentally important to life and defects in the process are associated with cancer, neurological disease and birth defects. Animals and fungi accomplish cytokinesis by constriction of an actomyosin contractile ring built from force-producing myosin motor proteins, actin filaments and other com- ponents. While much is established about the molecular parts it remains much less clear how these parts coordinate to produce a functional contractile machine. This has been difficult because experimentally mea- suring how the parts are spatiotemporally organized is challenging and mathematical modeling is needed to translate hypothesized arrangements into key observables such as ring constriction rate. This research project is a program of mathematical modeling and computational simulation focusing on fission yeast as a model sys- tem to establish principles of cytokinesis which may be general since many proteins involved are conserved between yeast and animals. The modeling will proceed as part of a tight theory-experiment collaboration with an experimental colleague studying yeast cytokinesis. A 3-phase strategy of increasing complexity will be adopted, starting with a simpler contractile system and ending with the full complexity of yeast constriction which occurs concomitantly with septation, the deposition of cell wall material between daughter cells. Phase A will consist in a study of stationary mammalian cell stress fibers, contractile actomyosin structures important in wound healing and other contexts. Stress fibers are relatively well characterized and their kinetics have been directly measured. Phase B will address yeast protoplasts, cells lacking cell wall in which ring constric- tion can occur without the complication of septation. In phase C constriction-septation in wild type yeast will be studied. The long term goals are to establish mechanisms of contractile force generation and kinetics in stress fibers and the fission yeast contractile ring and to determine the commonality between these systems. The specific aims of the modeling are: (i) To test hypothetical arrangements and turnover rules of actin, myosin, actin nucleators/depolymerization agents and other key components. In particular, to determine whether ar- rangements are sarcomeric (periodic, muscle-like) or non-sarcomeric (random) in the ring and stress fibers. (ii) To test the hypothesis that actin turnover is regulated by internal stresses. (iii) To apply models to predict outcomes of laser ablation experiments and spontaneous severing events which can reveal otherwise hidden features of actomyosin structures. Laser ablation experiments have already been performed on stress fibers. (iv) To test the hypothesis that the ring regulates septum growth in wild type yeast constriction. These aims will be accomplished by modeling efforts in a continuous dialog with experiments aiming to reveal new structural and kinetic features of the cytokinetic contractile ring. PUBLIC HEALTH RELEVANCE: Cytokinesis is the partitioning of a cell into two daughter cells at the end of the cell cycle. Its malfunction is associated with cancer, neurological disease and birth defects. The project aims to advance understanding of cytokinesis in yeast and cytokinesis mechanisms in general which will aid development of therapies for cytokinesis-related pathologies.

描述（由申请人提供）：胞质分裂是终止细胞周期的过程，其中母细胞的细胞质一分为二。作为细胞分裂的关键步骤，它对生命至关重要，并且该过程中的缺陷与癌症，神经系统疾病和出生缺陷有关。动物和真菌通过收缩由产生力的肌球蛋白马达蛋白、肌动蛋白丝和其他成分构成的肌动球蛋白收缩环来完成胞质分裂。虽然关于这些分子部分的研究已经有了很大的进展，但这些部分如何协调以产生一个功能性的收缩机器仍然不太清楚。这是困难的，因为实验测量部件如何时空组织是具有挑战性的，并且需要数学建模来将假设的布置转化为关键的可观察量，例如环收缩率。本研究项目是一个数学建模和计算机模拟的项目，重点是以裂殖酵母为模型系统，建立胞质分裂的原理，这些原理可能是普遍的，因为许多蛋白质在酵母和动物之间是保守的。建模将继续作为一个紧密的理论实验合作的一部分，与实验同事研究酵母胞质分裂。将采用增加复杂性的3阶段策略，从一个更简单的收缩系统开始，以伴随着分隔（子细胞之间细胞壁物质的沉积）发生的酵母收缩的完全复杂性结束。A阶段将包括对静止的哺乳动物细胞应力纤维、在伤口愈合和其他情况下重要的收缩性肌动球蛋白结构的研究。应力纤维的特征相对较好，它们的动力学已被直接测量。阶段B将处理酵母原生质体，即缺乏细胞壁的细胞，在这种细胞中可以发生环收缩而没有分离的并发症。在阶段C中，将研究野生型酵母中的收缩-分隔。长期目标是建立应力纤维和裂变酵母收缩环中收缩力产生和动力学的机制，并确定这些系统之间的共性。建模的具体目的是：（i）测试肌动蛋白，肌球蛋白，肌动蛋白成核剂/解聚剂和其他关键组分的假设排列和周转规则。特别是，以确定在环和应力纤维中的排列是肌节的（周期性的，肌肉样的）还是非肌节的（随机的）。(ii)为了验证肌动蛋白周转受内应力调节的假设。(iii)应用模型预测激光消融实验和自发切割事件的结果，这些事件可以揭示肌动球蛋白结构的其他隐藏特征。激光烧蚀实验已经在应力纤维上进行。(iv)为了检验环调节野生型酵母缢痕中隔膜生长的假设。这些目标将通过与旨在揭示细胞动力学收缩环的新结构和动力学特征的实验进行连续对话中的建模工作来实现。 公共卫生相关性：胞质分裂是在细胞周期结束时细胞分裂为两个子细胞。它的功能障碍与癌症、神经系统疾病和出生缺陷有关。该项目旨在促进对酵母胞质分裂和胞质分裂机制的理解，这将有助于开发与胞质分裂相关的病理学疗法。