Systems Biology analysis of biological timers and inflammation

生物计时器和炎症的系统生物学分析

• 批准号: BB/K003097/1
• 负责人: Michael White
• 金额: $ 530.13万
• 依托单位: University of Manchester
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2013
• 资助国家: 英国
• 起止时间: 2013 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FK003097%2F1
• 关键词: Systems; Biology; analysis; biological; timers

As we get older our immune system tends to get weaker and it becomes increasingly difficult to shake off diseases. At the same time we tend to develop arthritis and other auto-immune diseases which are localised instances of uncontrolled inflammation. In this grant application our multidisciplinary team of scientists consisting of physiologists, biologists, mathematicians and computer scientists aim to look at a very important signalling system NF-kappaB. This system plays an important role in stress and the immune responses and determines the fate of cells in the body, which is essential for general health and wellbeing. We will use a combined experimental and mathematical approach to analyse integrated systems that control NF-kappaB signalling in normal cells and tissues. We found that NF-kappaB carries signal information in the timing of its movements between the nucleus and cytoplasm. The timing of these movements determines which genes are switched on. We now wish to understand how this key process of NFkappaB signalling is controlled through normal life. How is it controlled by the cell division cycle, and how is it controlled by the sleep-wake cycle of the 24 h circadian clock.Recently, we have found that the speed of the oscillations in the NF-kappaB signalling system are very temperature sensitive in the physiological and fever range between 35 and 40 degrees C. This also appears to markedly change the pattern of which genes are switched on or off. Our work so far has been in cell lines grown in the laboratory and we now wish to investigate NF-kappaB signalling in normal cells taken from transgenic mice that have fluorescently labelled NF-kappaB proteins. We will use these cells to determine the NF-kappaB response to temperature, a range of physiological stimuli including glucocorticoids (which are often used in inflammatory treatment), to screen small molecule drugs to find ones that modulate the response and to study the quantitative relationships with the cell cycle and the circadian clock. The data from these experiments and others published in the literature will be used to build integrated mathematical models that can predict important aspects of cell, tissue and animal physiology relevant to understanding the maintenance of a healthy organism and how this may change with age.Key aims will be to understand how the clock and cell cycle together affect the timing and level of NF-kappaB signalling and which target genes are switched on. One of the NF-kappaB family of proteins, p105 encoded by the NFkB1 gene, has been found to cause faster ageing in mice when this gene is missing (Mann and von Ziglnicki, personal communication). We wish to investigate whether changes in NF-kappaB dynamics are involved in this ageing condition. Therefore, we will make a BAC reporter for p105 with fluorescent fusions at either end of the protein.We are an ideal team to perform this work, because we have complementary interdisciplinary skills in cell imaging, image analysis, molecular cell biology, physiology, genomics, bioinformatics and mathematical modelling. A core part of the team has an excellent track record of working together to analyse the NF-kappaB signalling system. In addition, this new project brings in new team members with considerable expertise in animal physiology, circadian clocks and endocrinology.

随着年龄的增长，我们的免疫系统变得越来越弱，越来越难以摆脱疾病。与此同时，我们往往会患上关节炎和其他自身免疫性疾病，这些疾病都是局部无法控制的炎症。在这项拨款申请中，我们由生理学家、生物学家、数学家和计算机科学家组成的多学科科学家团队旨在研究一个非常重要的信号系统NF-kappaB。该系统在压力和免疫反应中起着重要作用，并决定体内细胞的命运，这对整体健康和幸福至关重要。我们将使用实验和数学相结合的方法来分析控制正常细胞和组织中NF-kappaB信号的集成系统。我们发现NF-kappaB在细胞核和细胞质之间的运动时间中携带信号信息。这些运动的时间决定了哪些基因被激活。我们现在希望了解NFkappaB信号传导的这个关键过程是如何在正常生活中被控制的。它是如何被细胞分裂周期控制的，又是如何被24小时生物钟的睡眠-觉醒周期控制的。最近，我们发现NF-kappaB信号系统的振荡速度在35到40摄氏度之间的生理和发热范围内对温度非常敏感。这似乎也显着改变了基因开启或关闭的模式。到目前为止，我们的工作是在实验室培养的细胞系中进行的，我们现在希望研究NF-kappaB信号在从荧光标记NF-kappaB蛋白的转基因小鼠中提取的正常细胞中的作用。我们将利用这些细胞来确定NF-kappaB对温度、包括糖皮质激素（常用于炎症治疗）在内的一系列生理刺激的反应，筛选小分子药物以找到调节反应的药物，并研究与细胞周期和生物钟的定量关系。来自这些实验和其他发表在文献中的数据将用于建立综合数学模型，该模型可以预测细胞、组织和动物生理学的重要方面，这些方面与了解健康生物体的维持以及这些方面如何随年龄变化有关。关键目标将是了解时钟和细胞周期如何共同影响NF-kappaB信号的时间和水平，以及哪些靶基因被打开。NFkB1基因编码的NF-kappaB蛋白家族中的一种p105被发现，当该基因缺失时，会导致小鼠更快衰老（Mann and von Ziglnicki, personal communication）。我们希望研究NF-kappaB动力学的变化是否与这种衰老状况有关。因此，我们将利用蛋白两端的荧光融合物制作p105的BAC报告基因。我们是完成这项工作的理想团队，因为我们在细胞成像、图像分析、分子细胞生物学、生理学、基因组学、生物信息学和数学建模方面具有互补的跨学科技能。该团队的核心成员在分析NF-kappaB信号系统方面有着良好的合作记录。此外，这个新项目带来了在动物生理学、生物钟和内分泌学方面具有相当专业知识的新团队成员。

项目成果

Investigating IL-1ß Secretion Using Real-Time Single-Cell Imaging.

使用实时单细胞成像研究 IL-1 分泌。

• DOI: 10.1007/978-1-4939-3566-6_4
• 发表时间: 2016
• 期刊: Methods in molecular biology (Clifton, N.J.)
• 作者: Diamond C

Understanding the dynamics of Toll-like Receptor 5 response to flagellin and its regulation by estradiol.

了解Toll样受体5对鞭毛蛋白的反应及其对雌二醇的调节的动力学。

• DOI: 10.1038/srep40981
• 发表时间: 2017-01-23
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Caballero I;Boyd J;Almiñana C;Sánchez-López JA;Basatvat S;Montazeri M;Maslehat Lay N;Elliott S;Spiller DG;White MR;Fazeli A
• 通讯作者: Fazeli A

Fenamate NSAIDs inhibit the NLRP3 inflammasome and protect against Alzheimer's disease in rodent models.

• DOI: 10.1038/ncomms12504
• 发表时间: 2016-08-11
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Daniels MJ;Rivers-Auty J;Schilling T;Spencer NG;Watremez W;Fasolino V;Booth SJ;White CS;Baldwin AG;Freeman S;Wong R;Latta C;Yu S;Jackson J;Fischer N;Koziel V;Pillot T;Bagnall J;Allan SM;Paszek P;Galea J;Harte MK;Eder C;Lawrence CB;Brough D
• 通讯作者: Brough D

Integration of Kinase and Calcium Signaling at the Level of Chromatin Underlies Inducible Gene Activation in T Cells.

• DOI: 10.4049/jimmunol.1602033
• 发表时间: 2017-10-15
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Brignall R;Cauchy P;Bevington SL;Gorman B;Pisco AO;Bagnall J;Boddington C;Rowe W;England H;Rich K;Schmidt L;Dyer NP;Travis MA;Ott S;Jackson DA;Cockerill PN;Paszek P
• 通讯作者: Paszek P

Gene-Specific Linear Trends Constrain Transcriptional Variability of the Toll-like Receptor Signaling.

• DOI: 10.1016/j.cels.2020.08.007
• 发表时间: 2020-09-23
• 期刊: Cell systems
• 影响因子: 9.3
• 作者: Bagnall J;Rowe W;Alachkar N;Roberts J;England H;Clark C;Platt M;Jackson DA;Muldoon M;Paszek P
• 通讯作者: Paszek P