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

100多年来，生物学家一直在研究细胞如何将染色体移动到正确的位置，从而在有丝分裂过程中成功地进行细胞分裂。由于有丝分裂依赖于数十种蛋白质类型，因此预测有丝分裂如何进行是具有挑战性的。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，细胞首先建立一个起重机（有丝分裂纺锤体），然后用它来移动大的物体（染色体）到正确的位置（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纺锤体，新的算法正在模拟有丝分裂作为一个整体。该模型与裂变酵母实验相结合。这个项目超越了以前的工作，解决闭合有丝分裂，其中核膜保持完整，染色体分离和核分裂一起发生。为了从整体上理解闭合有丝分裂，该项目正在确定纺锤体影响包膜和包膜影响纺锤体成功有丝分裂的机制。建立这个更现实的有丝分裂中同时发生核分裂和染色体分离的模型，将最终允许研究生命中的有丝分裂，特别是核膜功能（封闭、半开放和开放有丝分裂）。从长远来看，理解细胞如何分裂对于帮助纠正细胞分裂中的错误是很重要的。该项目正在发展生物物理学、细胞生物学和数学生物学的跨学科教育。该项目正在扩展一个国际在线生物物理学研讨会，使研究成果在精英机构之外广泛地免费获得，从而扩大生物物理学的参与范围。该项目是通过将膜和细胞骨架建模工具结合在一起来模拟闭合有丝分裂，这是具有挑战性的集成和实现可处理的算法。第一个目标是扩展有丝分裂模型，使其包括一个可变形的弹性核膜，将纺锤体和染色体与核膜的边界积分和三角膜模型结合起来。第二个目标是通过模拟和测量包膜形状、纺锤体动力学和核膜扰动下细胞中的染色体运动，确定核膜力和变形如何在封闭有丝分裂中驱动成功的染色体分离。该项目正在开发新的算法和软件来模拟膜-细胞骨架的相互作用，这是目前难以建模的。该奖项反映了美国国家科学基金会的法定使命，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。

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.