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

100多年来，生物学家一直致力于弄清楚细胞如何将染色体移动到正确的位置，以实现成功的细胞分裂，这一过程被称为有丝分裂。因为有丝分裂依赖于几十种蛋白质类型，所以预测有丝分裂是如何工作的是具有挑战性的。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)。从关键分子子集的细节开始，包括染色体和有丝分裂纺锤体，新的算法将有丝分裂作为一个整体进行模拟。该模型是通过在分裂酵母中的实验携手开发的。这个项目超越了以前的工作，解决了闭合有丝分裂，在闭合有丝分裂中，核膜保持完整，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，这个项目是为了确定纺锤体影响包膜和包膜影响纺锤体的机制，以实现成功的有丝分裂。建立这种在有丝分裂中同时进行核分裂和染色体分离的更现实的模型，最终将有助于研究生命中的有丝分裂，特别是核膜功能(闭合、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获得，并免费，扩大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结合在一起来对闭合有丝分裂进行建模，这些工具很难与易于处理的算法集成和实施。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膜，将纺锤体和染色体与核膜的边界积分和三角膜模型相结合。第二个目标是通过建模和测量核被膜形状、纺锤体动力学和核被膜扰动细胞中的染色体运动，确定核包膜力和变形如何驱动闭合有丝分裂中成功的染色体分离。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智力优势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.