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: 2133243
• 负责人: Meredith Betterton
• 金额: $ 110.32万
• 依托单位: University of Colorado at Boulder
• 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=2133243&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，生物学家一直在努力理解细胞如何在称为有丝分裂的过程中将染色体转移到正确的细胞分裂位置。由于有丝分裂取决于数十种蛋白质类型，因此预测有丝分裂的工作原理是一项挑战。因此，该项目正在建立有丝分裂的数学模型。有丝分裂的类比是该细胞首先建立起重机（有丝分裂主轴），然后使用它将大物体（染色体）移至其正确的位置（染色体分离）。 从关键分子子集的细节开始，包括染色体和有丝分裂主轴，新算法正在模拟有丝分裂。 该模型与裂变酵母中的实验并驾齐驱。该项目超越了以前的工作，以解决封闭的有丝分裂，其中核包膜保持不变，并且染色体隔离和核划分共同出现。为了了解整个封闭有丝分裂，该项目正在识别纺锤体影响包膜的机制，并且包膜影响成功有丝分裂的主轴。在有丝分裂中建立这种更现实的核分裂和染色体分离的模型最终将允许研究跨越生命的有丝分裂，尤其是在核隐络功能方面（封闭，半开放和开放有丝分裂）。从长远来看，了解细胞分裂在有助于纠正细胞分裂中的误差的长期以来很重要。该项目正在开发生物物理学，细胞生物学和数学生物学方面的跨学科教育。该项目正在扩展一项国际，在线生物物理学研讨会，该研讨会使研究结果在精英机构外部广泛可用，并且无需付出任何代价，从而扩大了对生物物理学的参与。该项目通过将膜和细胞骨架建模工具汇总在一起，对封闭有丝裂作用进行建模，这些工具与易于易质算法的挑战和实现。 第一个目标是将有丝分裂模型扩展到包括可变形的弹性核包膜，以将纺锤体和染色体与核包膜的边界综合和三角形膜模型相结合。第二个目标是通过建模和测量包膜形状，纺锤体动力学和染色体运动，在细胞中对核包膜扰动进行建模和测量，核包膜力和变形如何驱动封闭有丝分裂的成功染色体分离。 该项目正在开发新的算法和软件，以模拟膜 - 细胞骨架相互作用，这些相互作用很难建模。该奖项反映了NSF的法定任务，并被认为是值得通过基金会的知识分子优点和更广泛的影响来通过评估来支持的。