Modeling Contractile Ring Constriction in Fission Yeast

描述（由申请人提供）：细胞质分裂是细胞周期结束的过程，在这个过程中，母细胞质分裂成两个。作为细胞分裂的一个关键步骤，它对生命至关重要，而这个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肌动蛋白收缩环来完成细胞分裂。肌动蛋白收缩环是由产生力量的肌动蛋白、运动蛋白、肌动蛋白丝和其他成分组成的。虽然对分子部分已经有了很多了解，但这些部分是如何协调生产出一个功能齐全的收缩机器的，仍然不太清楚。这是很困难的，因为实验意味着确定部件的时空组织方式是具有挑战性的，并且需要数学建模来将假设的排列转化为关键的可观测值，如环收缩率。本研究项目是一个数学建模和计算模拟的项目，重点研究分裂酵母作为一个模型系统，以建立细胞分裂的原理，这可能是普遍的，因为许多蛋白质在酵母和动物之间是保守的。建模将作为与研究酵母细胞分裂的实验同事紧密理论实验合作的一部分进行。将采用一个增加复杂性的3阶段策略，从一个更简单的收缩系统开始，以酵母收缩的完全复杂性结束，酵母收缩伴随着分离，细胞壁物质在子细胞之间的沉积。A阶段将包括静止哺乳动物细胞应激纤维的研究，在伤口愈合和其他情况下重要的收缩肌动球蛋白结构。应力纤维的表征相对较好，其动力学已被直接测量。阶段B将处理酵母原生质体，细胞缺乏细胞壁，其中环收缩可以发生，而没有分离的并发症。C期将研究野生型酵母的缩窄-分离。长期目标是在应力纤维和裂变酵母收缩环中建立收缩力产生和动力学机制，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、肌凝蛋白、肌动蛋白成核剂/解聚剂和其他关键成分的假设排列和周转规则。特别是，确定环纤维和应力纤维的排列是肌肉性的（周期性的，肌肉样的）还是非肌肉性的（随机的）。（ii）检验肌动蛋白周转受内应力调节的假设。（iii）应用模型预测激光烧蚀实验和自发切断事件的结果，从而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）验证野生型酵母菌缩窄过程中该环调节隔膜生长的假设。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的连续对话中的建模努力来实现。

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.