Collaborative Research: MODULUS: Nuclear envelope shape change coordination with chromosome segregation in mitosis in fission yeast

合作研究：MODULUS：核膜形状变化与裂殖酵母有丝分裂中染色体分离的协调

• 批准号: 2133276
• 负责人: Mary Elting
• 金额: $ 33.68万
• 依托单位: North Carolina State University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-15 至 2026-05-31
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2133276&HistoricalAwards=false
• 关键词: Collaborative; Research; MODULUS; Nuclear; envelope

For over 100 years, biologists have worked to make sense of how cells move chromosomes to the correct locations for successful cell division in a process known as mitosis. Because mitosis depends on dozens of protein types, it is challenging to predict how mitosis works. Therefore, this project is building a mathematical model of mitosis. An analogy for mitosis is that the cell first builds a crane (the mitotic spindle) and then uses it to move large objects (the chromosomes) to their correct places (chromosome segregation). Starting with the details of a subset of the key molecules, including the chromosomes and the mitotic spindle, new algorithms are simulating mitosis as a whole. The model is developed hand-in-hand with experiments in fission yeast. This project is going beyond previous work to address closed mitosis, in which the nuclear envelope remains intact, and chromosome segregation and nuclear division occur together. To understand closed mitosis as a whole, this project is identifying the mechanisms by which the spindle affects the envelope and the envelope affects the spindle for successful mitosis. Building this more realistic model of simultaneous nuclear division and chromosome segregation in mitosis will ultimately allow study of mitosis across life, particularly in nuclear envelope function (closed, semi-open, and open mitosis). Understanding how cells divide is important in the long run for helping correct errors in cell division. The project is developing interdisciplinary education in biophysics, cellular biology, and mathematical biology. The project is extending an international, online biophysics seminar that makes research results broadly available outside elite institutions and at no cost, broadening participation in biophysics.This project is modeling closed mitosis by bringing together membrane and cytoskeletal modeling tools, which are challenging to integrate and implement with tractable algorithms. The first objective is extending a model of mitosis to include a deformable elastic nuclear envelope, to integrate the spindle and chromosomes with boundary-integral and triangulated-membrane models of the nuclear envelope. The second objective is to identify how nuclear envelope forces and deformation drive successful chromosome segregation in closed mitosis, by modeling and measuring envelope shape, spindle dynamics, and chromosome movement in cells with perturbations to the nuclear envelope. The project is developing new algorithms and software for simulation of membrane-cytoskeleton interactions, which are difficult to model currently.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

100多年来，生物学家一直致力于弄清楚细胞如何将染色体移动到正确的位置，以便在被称为有丝分裂的过程中成功进行细胞分裂。由于有丝分裂依赖于几十种蛋白质类型，因此预测有丝分裂是如何工作的具有挑战性。因此，本项目正在建立有丝分裂的数学模型。有丝分裂的一个类比是，细胞首先建造一个起重机（有丝分裂纺锤体），然后用它将大的物体（染色体）移动到正确的位置（染色体分离）。 从关键分子的一个子集的细节开始，包括染色体和有丝分裂纺锤体，新的算法正在模拟整个有丝分裂。 该模型是与裂变酵母中的实验一起开发的。该项目超越了以前的工作，以解决封闭的有丝分裂，其中核被膜保持完整，染色体分离和核分裂同时发生。为了从整体上理解闭合有丝分裂，本项目确定纺锤体影响包膜以及包膜影响纺锤体以实现成功有丝分裂的机制。建立这种更现实的模型，同时核分裂和染色体分离的有丝分裂将最终允许研究整个生命的有丝分裂，特别是在核膜功能（封闭，半开放和开放有丝分裂）。从长远来看，了解细胞如何分裂对于帮助纠正细胞分裂中的错误非常重要。该项目正在发展生物物理学、细胞生物学和数学生物学方面的跨学科教育。该项目正在扩展一个国际在线生物物理研讨会，使研究成果在精英机构之外免费广泛提供，扩大了生物物理学的参与范围。该项目正在通过汇集膜和细胞骨架建模工具来建模闭合有丝分裂，这些工具具有挑战性，难以与易于处理的算法集成和实现。 第一个目标是扩展有丝分裂的模型，包括一个可变形的弹性核膜，整合纺锤体和染色体与边界积分和三角形膜模型的核膜。第二个目标是确定如何核膜力和变形驱动成功的染色体分离在封闭的有丝分裂，通过建模和测量信封的形状，纺锤体动力学，和染色体运动的细胞与核膜的扰动。 该项目正在开发新的算法和软件，用于模拟目前难以建模的膜-细胞骨架相互作用。该奖项反映了NSF的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。