Circadian and cell cycle clock systems in cancer

癌症中的昼夜节律和细胞周期时钟系统

• 批准号: BB/I004521/1
• 负责人: David Rand
• 金额: $ 31.44万
• 依托单位: University of Warwick
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2010
• 资助国家: 英国
• 起止时间: 2010 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FI004521%2F1
• 关键词: Circadian; cell; cycle; clock; systems

The circadian clock and the cell cycle are dynamic biological events. Over the last decades, our understanding of the molecular mechanisms underlying these systems has greatly improved, with extensive development and use of mathematical models. In sharp contrast, little is known about how these two crucial oscillators interact, and how these interactions affect cellular proliferation, DNA repair and apoptosis, in normal or cancer cells. On the one hand, the disruption of circadian clocks impairs cell physiology and quality of life. On the other hand, disruption of cell cycle, DNA repair or apoptosis can profoundly impact on cell and organism survival. Experimental and clinical data show that circadian disruption accelerates malignant proliferation, and that DNA damage can reset the circadian clock. Therefore, a central question to be addressed is how interactions between the circadian clock and the cell cycle affect cellular proliferation and (geno)toxic sensitivity in normal and cancer cells, and how this knowledge translates into new prevention or treatments. C5Sys integrates experimental, mathematical and bioinformatic approaches to explore the dynamic links between circadian clock and cell cycle, and their relevance for normal and malignant cell physiology and proliferation. C5Sys maps these interactions and the coupling between both oscillatory systems through a systems biology (SB) approach. C5Sys investigates how the circadian clock can act as a gatekeeper of cell cycle progression in normal and cancer cells. This will result in the identification of novel targets for these clock-cell cycle interactions, whose internal or external perturbations could affect cancer progression and/or could impact on cancer treatments. C5Sys assembles 7 European teams with extensive complementary background and wide international scientific recognition in the fields of circadian clocks, cancer dynamics, DNA repair and apoptosis, as well as bioinformatics, mathematical models and time series analysis and imaging. C5Sys is organised in 5 workpackages (WP), with tight mutual interactions between experimental, mathematical and statistical teams within and between WPs. C5Sys will: 1) map critical interaction nodes between circadian and cell cycle clocks, whose disruption is relevant for altered or malignant proliferation; 2) characterize the time scales in the signalling pathways, which are critical for the coupling of both biological clocks, including those operating at higher frequency; 3) determine the rhythmic signals whose disruption participates in malignant growth; 4) provide an integrated 'proliferative' cellular model incorporating circadian and cell cycle clocks and underlying rhythmic signalling pathways; 5) determine model properties in cancer cells; 6) probe the relevance of targeted interventions for disrupting or reinforcing the coupling of circadian clock and cell cycle in silico; and 7) attempt to provide in vitro and in vivo proof of principles of the relevance of model-based chronotherapeutic interventions. The novel cell lines, biomarker monitoring methods and mathematical tools, which will be developed as a result of this proposal, will circumvent current bottlenecks in the exploration of temporal changes in functional genomics and their potential therapeutic relevance for cancer. C5sys results will trigger 1) innovative chronotherapeutic research for several human diseases involving circadian and cell cycle systems and 2) dedicated technology development for scientific and biomedical applications.

生物钟和细胞周期是动态的生物事件。在过去的几十年里，随着数学模型的广泛发展和使用，我们对这些系统背后的分子机制的理解已经大大提高。与此形成鲜明对比的是，人们对这两个关键振荡器如何相互作用，以及这些相互作用如何影响正常细胞或癌细胞中的细胞增殖、DNA 修复和凋亡知之甚少。一方面，生物钟的破坏会损害细胞生理和生活质量。另一方面，细胞周期的破坏、DNA 修复或细胞凋亡会对细胞和生物体的生存产生深远的影响。实验和临床数据表明，昼夜节律紊乱会加速恶性增殖，而 DNA 损伤可以重置生物钟。因此，需要解决的一个核心问题是生物钟和细胞周期之间的相互作用如何影响正常细胞和癌细胞的细胞增殖和（基因）毒性敏感性，以及这些知识如何转化为新的预防或治疗。 C5Sys 整合了实验、数学和生物信息学方法，探索生物钟和细胞周期之间的动态联系，及其与正常和恶性细胞生理和增殖的相关性。 C5Sys 通过系统生物学 (SB) 方法绘制这些相互作用以及两个振荡系统之间的耦合。 C5Sys 研究生物钟如何充当正常细胞和癌细胞中细胞周期进程的看门人。这将导致识别这些时钟细胞周期相互作用的新靶标，其内部或外部扰动可能影响癌症进展和/或可能影响癌症治疗。 C5Sys 汇集了 7 个欧洲团队，他们在生物钟、癌症动力学、DNA 修复和细胞凋亡、以及生物信息学、数学模型和时间序列分析和成像领域拥有广泛的互补背景和广泛的国际科学认可。 C5Sys 由 5 个工作包 (WP) 组成，WP 内部和之间的实验、数学和统计团队之间具有紧密的互动。 C5Sys 将：1）绘制昼夜节律和细胞周期时钟之间的关键相互作用节点，其破坏与改变或恶性增殖相关； 2）表征信号通路中的时间尺度，这对于两个生物钟（包括在较高频率下运行的生物钟）的耦合至关重要； 3）确定其破坏参与恶性生长的节律信号； 4) 提供集成的“增殖”细胞模型，包含昼夜节律和细胞周期时钟以及潜在的节律信号通路； 5) 确定癌细胞的模型特性； 6) 探讨有针对性的干预措施在计算机模拟中破坏或加强生物钟和细胞周期耦合的相关性； 7) 尝试提供基于模型的时间治疗干预的相关性原理的体外和体内证明。由于该提案而开发的新型细胞系、生物标志物监测方法和数学工具将绕过当前探索功能基因组学时间变化及其与癌症的潜在治疗相关性的瓶颈。 C5sys 结果将触发 1) 针对涉及昼夜节律和细胞周期系统的多种人类疾病的创新时间治疗研究，以及 2) 科学和生物医学应用的专门技术开发。

项目成果

Coupling between the Circadian Clock and Cell Cycle Oscillators: Implication for Healthy Cells and Malignant Growth.

昼夜节律时钟和细胞周期振荡器之间的耦合：对健康细胞和恶性生长的影响。

• DOI: http://dx.10.3389/fneur.2015.00096
• 发表时间: 2015
• 期刊: Frontiers in neurology
• 作者: Feillet C

TimeTeller: a New Tool for Precision Circadian Medicine and Cancer Prognosis

TimeTeller：精准昼夜节律医学和癌症预测的新工具

• DOI: http://dx.10.1101/622050
• 发表时间: 2019
• 作者: Vlachou D

Cyclin-dependent kinase inhibitor p20 controls circadian cell-cycle timing.

细胞周期蛋白依赖性激酶抑制剂 p20 控制昼夜节律细胞周期时间。

• DOI: http://dx.10.1073/pnas.1217912110
• 发表时间: 2013
• 期刊: Proceedings of the National Academy of Sciences of the United States of America
• 影响因子: 11.1
• 作者: Laranjeiro R

Phase locking and multiple oscillating attractors for the coupled mammalian clock and cell cycle.

用于耦合哺乳动物时钟和细胞周期的锁相和多个振荡吸引子。

• DOI: http://dx.10.1073/pnas.1320474111
• 发表时间: 2014
• 期刊: Proceedings of the National Academy of Sciences of the United States of America
• 影响因子: 11.1
• 作者: Feillet C