Systems-level characterization of mammalian cell cycle transitions

在人类的发育和生长过程中，细胞必须以有序和受控的方式增殖，才能形成成人的身体。细胞周期是一系列事件，导致一个亲本细胞形成两个细胞。重要的是，每个子代细胞必须与亲代细胞完全相同，因此细胞周期的成功完成需要精确复制和分发DNA中包含的遗传信息。细胞周期事件是由大量相互作用和共同发挥作用的蛋白质编排的，以确保细胞周期得到精确控制。分子生物学家已经发现了许多这样的细胞周期蛋白。值得注意的是，这些蛋白质及其相互作用方式从酵母到人类都高度保守。然而，由于该系统非常复杂，目前还不清楚所有这些蛋白质是如何共同推动细胞周期向前发展的。为了利用这些来之不易的关于控制细胞周期的机制的信息，必须使用计算工具来可靠地模拟系统的综合行为。酵母和早期胚胎中相对简单的细胞周期控制系统的数学模型显示，细胞周期控制网络具有“开关状”系统的特性。这些效应使得细胞周期状态之间的转换突然(类似开关)、单向(不可逆)和可控(对错误检测机制敏感)。当细胞检测到特定过程的执行出现问题时，它可以通过抑制开关来阻止向下一个细胞周期阶段的过渡。这种类似开关的行为已经在单细胞生物体(例如酵母)的所有细胞周期转变中得到了实验证明。然而，目前尚不清楚这些原理是否也在更复杂的细胞(例如人类)的细胞周期控制中得到体现。因此，在这个假设驱动的研究计划中，我们建议测试更复杂的人类细胞细胞周期控制网络的设计原理。我们将使用高科技实验和理论工具相结合的方式来解决这一问题。为了实现这一目标，将组建一个由生物化学家、细胞生物学家和模型师组成的跨学科团队。了解哺乳动物细胞中细胞周期控制的原理对于理解人类疾病至关重要。例如，在癌症中，细胞失去对细胞周期的控制，反复复制，形成肿瘤。通过了解细胞周期是如何控制的，我们可以开发新的方法来恢复对癌细胞的细胞周期控制，并阻止它们失控地复制。相反，如果体内干细胞的细胞复制受到损害，分化细胞的更新就会延迟，这是导致衰老过程的原因之一。由于许多新兴的干细胞疗法依赖于对细胞复制的精确控制，该领域也将从我们的研究中受益。因此，我们的研究提案涉及BBSRC的两个基本战略优先事项：“生物科学的系统方法”和“生命过程中的老龄化”。

During human development and growth, cells must proliferate in an ordered and controlled manner to form the adult body. The cell cycle is a series of events that results in two cells forming from one parent cell. Importantly each daughter cell must be identical to the parent cell, thus successful completion of the cell cycle requires the precise copying and distribution of genetic information contained within DNA. Cell cycle events are orchestrated by a large array of proteins that interact and function together to ensure the cell cycle is precisely controlled. Molecular biologists have uncovered many of these cell cycle proteins. Remarkably, these proteins and how they interact are highly conserved from yeasts to humans. However because the system is very complex, it is not obvious how all these proteins work together to drive the cell cycle forward. In order to use this hard-won information about the mechanisms controlling the cell cycle, computational tools are necessary to reliably simulate the integrated behaviour of the system. Mathematical models of relatively simple, cell-cycle control systems in yeasts and early embryos revealed that the cell cycle control network has the property of a "switch-like" system. These effects make the transitions between cell cycle states abrupt (switch-like), unidirectional (irreversible) and controllable (sensitive to error-detection mechanisms). When the cell detects a problem with the execution of a particular process, it can block the transition to the next cell cycle stage by inhibiting the switch. This switch-like behaviour has been demonstrated experimentally for all cell cycle transitions in single-celled organisms (e.g. yeasts). However it is still unknown whether these principles are also manifested in the cell cycle control of more complex cells (e.g. in humans). Therefore in this hypothesis-driven research programme, we propose to test the design principles of more complex cell cycle control network of human cells.We will use a combination of high-tech experimental and theoretical tools to tackle this problem. In order to achieve this goal, an interdisciplinary team of biochemists, cell biologists and modellers will be assembled. Understanding the principles of cell cycle controls in mammalian cells is vital to the understanding of human disease. For example, in cancer, cells lose control of the cell cycle and replicate repeatedly, forming a tumour. By understanding how the cell cycle is controlled, we can develop new ways to restore cell cycle control to cancer cells and stop them replicating out of control. In contrast, if the cellular reproduction of stem cells in the body is compromised, renewal of differentiated cells is retarded which is one of the reasons underlying the ageing process. Since many emerging stem cell therapies rely on the precise control of cell replication this field will also benefit from our research. Therefore our research proposal addresses two fundamental Strategic Priorities of BBSRC: "Systems Approaches to the Biosciences" and "Ageing across life-course".