Studying the control of Cytokinesis as an Evolved Complex System

描述（由申请人提供）：本申请中提出的工作的广泛目标是使用出芽酵母作为模式生物来理解胞质分裂途径的设计原理和进化动力学。胞质 一个细胞一分为二的物理分裂 是细胞分裂的最后关键步骤这一过程的复杂性和重要性使得胞质分裂成为细胞生物学中广泛研究但仍未解决的问题之一。我们和其他人以前表明，芽殖酵母利用肌动球蛋白为基础的收缩环分裂，在动物细胞。这一发现使我们能够使用这个高度易处理的模型来理解胞质分裂的基本原理和分子途径。虽然我们以前的工作遵循传统的方法，经典的遗传和生化分析，在这里，我们建议采取独特的网络建模，定量成像，进化分析，基因组和表达微阵列的组合，以了解分子复杂性的设计原则。在这项研究中要回答的主要问题是：1）一个复杂的分子相互作用网络，涉及信号分子和细胞骨架蛋白，发生在有丝分裂过程中，如何确保不对称的细胞分裂在空间和时间上精确的方式; 2）如何，在响应大扰动，这种细胞分裂系统可以迅速演变，以保持其所需的功能。公共卫生相关性：胞质分裂是细胞分裂的关键事件，是真核生物生长和发育的基础。胞质分裂的失败导致多倍化，这是癌细胞的一个共同特征，被认为有助于基因组不稳定和癌症的体细胞进化。不对称胞质分裂对于胚胎不对称性的产生和不同细胞类型的分化也很重要3。因此，了解胞质分裂的机制和调控对于治疗或预防癌症和发育异常等疾病具有重要意义。1..斯托霍瓦角& Pellman，D.从多倍体到非整倍体，基因组不稳定性和癌症。Nat Rev Mol Cell Biol 5，45-54（2004）. 2.. Fujiwara，T.等. Cytokinesis failure generating tetraploid promotes tumorigenesis in p53-null cells. Nature 437，1043-1047（2005）. 3.斯特罗姆湾秀丽隐杆线虫胚胎早期胚胎发生过程中细胞多样性的产生。Int. Rev. Cyt. 114，81-123（1989）。

DESCRIPTION (provided by applicant): The broad goal of the work proposed in this application is to understand the design principles and evolutionary dynamics of the cytokinesis pathway using the budding yeast as the model organism. Cytokinesis the physical division of a cell in two is the last critical step of cell division. The complexity and importance of this process has made cytokinesis one of the extensively studied and yet still unsolved problems in cell biology. We and others previously showed that the budding yeast utilizes an actomyosin-based contractile ring to divide, as in animal cells. This finding allows us to use this highly tractable model to understand the basic principles and molecular pathways governing cytokinesis. Whereas our previous work followed a conventional approach of classical genetic and biochemical analyses, here we propose to take a unique combination of network modeling, quantitative imaging, evolutionary analysis, and genomic and expression microarrays, to understand the design principles underlying the molecular complexity. The main questions to be answered in this study are: 1) how a complex network of molecular interactions, involving signaling molecules and cytoskeletal proteins, which occur during mitosis, ensures asymmetric cell division in a spatially and temporally precise manner; and 2) how, in response to large perturbations, this cell division system could rapidly evolve to maintain its required functionality. PUBLIC HEALTH RELEVANCE: Cytokinesis is a crucial event in cell division, which is the basis for the growth and development of eukaryotic organisms. Failure in cytokinesis results in polyploidization, a common feature of cancer cells that is thought to contribute to genome instability and somatic evolution of cancer.1, 2. Asymmetric cytokinesis is also important for the generation of embryonic asymmetry and differentiation of diverse cell types3. Therefore, understanding the mechanism and regulation of cytokinsesis is important for treatment or prevention of diseases such as cancer and developmental abnormalities. 1.. Storchova, Z. & Pellman, D. From polyploidy to aneuploidy, genome instability and cancer. Nat Rev Mol Cell Biol 5, 45-54 (2004). 2.. Fujiwara, T. et al. Cytokinesis failure generating tetraploids promotes tumorigenesis in p53-null cells. Nature 437, 1043-1047 (2005). 3. Strome, S. Generation of cell diversity during early embryogenesis in the nematode Caenorhabditis elegans embryos. Int. Rev. Cyt. 114, 81-123 (1989).