Experimental and Computational Studies of Exit from Mitosis in Budding Yeast

描述（由申请人提供）：细胞生长、DMA合成、有丝分裂和细胞分裂的周期是细胞（和所有生物体）生长、发育和繁殖的基本过程。因此，了解真核细胞中控制这些过程的分子机制对科学和人类健康至关重要。分子生物学家已经非常成功地确定了参与这一控制系统的主要基因和蛋白质，特别是在遗传工具特别强大的酵母细胞中。事实上，分子细节是如此广泛，调控网络是如此复杂，以至于需要数学和计算方法来可靠地跟踪数十个基因，mRNA，蛋白质和多蛋白质复合物的相互作用。这种芽殖酵母细胞周期控制系统的模型已被证明是准确和预测。尽管如此，随着细胞周期控制机制的实验表征不断发展，模型也必须发展。在这项提案中，来自弗吉尼亚理工大学，洛克菲勒大学和分子肿瘤学研究所的理论家和实验学家组成的多学科团队寻求更好地了解细胞周期结束时对事件的分子控制，当复制的DMA分子被分配到分裂细胞的两半时，每个新形成的细胞都会收到每个DNA分子的一个且只有一个拷贝。如果分裂的细胞在这个过程中出错，那么新生细胞将继承过多或过少的DNA分子，这是某些疾病（如癌症）和某些出生缺陷的根本原因。研究人员将测量有丝分裂退出事件的分子相关性，并建立控制这些事件的信号通路的详细模型（有丝分裂退出网络，FEAR 1通路，DNA损伤检查点和纺锤体组装检查点）。所有模型都建立在实验观察的坚实基础上，它们对受控条件下的细胞分裂做出了清晰而新颖的预测。这些预测中的许多将由实验合作者进行测试。由于所有真核细胞似乎都采用相同的细胞周期调节的基本分子机制，因此在芽殖酵母中建模有丝分裂退出的成功将转化为对与人类健康相关的正常和异常细胞分裂的更好理解：例如，胚胎发育、组织再生、伤口愈合和致癌作用。

DESCRIPTION (provided by applicant): The cycle of cell growth, DMA synthesis, mitosis and cell division is the fundamental process by which cells (and all living organisms) grow, develop and reproduce. Hence, it is of crucial importance to science and human health to understand the molecular mechanisms that control these processes in eukaryotic cells. Molecular biologists have been extremely successful in identifying the major genes and proteins involved in this control system, especially in yeast cells where genetic tools are especially powerful. Indeed, the molecular details are so extensive and the regulatory network is so complicated that mathematical and computational methods are needed to reliably track the interactions of dozens of genes, mRNAs, proteins, and multi-protein complexes. Such a model of the cell cycle control system in budding yeast has proved to be both accurate and predictive. Nonetheless, as experimental characterization of cell-cycle control mechanisms continues to grow, the model must grow as well. In this proposal, a multi-disciplinary team of theoreticians and experimentalists from Virginia Tech, the Rockefeller University and the Institute for Molecular Oncology seeks a better understanding of the molecular controls over events at the end of the cell cycle, when replicated DMA molecules are partitioned to the two halves of a dividing cell so that each newly formed cell receives one and only one copy of each DNA molecule. If the dividing cell makes errors in this process, then newborn cells will inherit too many or too few DNA molecules, which is a root cause of some diseases-like cancer-and of some birth defects. The investigators will measure the molecular correlates of mitotic-exit events, and they will build detailed models of the signaling pathways that control these events (the mitotic-exit network, the 'FEAR1 pathway, the DNA-damage checkpoint, and the spindle assembly checkpoint). All models are built on a solid foundation of experimental observations, and they make clear and novel predictions about cell division under controlled conditions. Many of these predictions will be tested by the experimental collaborators. Because all eukaryotic cells seem to employ the same fundamental molecular machinery of cell cycle regulation, success in modeling mitotic exit in budding yeast will translate into better understanding of normal and aberrant cell division of relevance to human health: e.g., embryonic development, tissue regeneration, wound healing, and carcinogenesis.