MRC Transition Support CSF John Blaikley

MRC 过渡支持 CSF John Blaikley

基本信息

  • 批准号:
    MR/T032529/1
  • 负责人:
  • 金额:
    $ 39.92万
  • 依托单位:
  • 依托单位国家:
    英国
  • 项目类别:
    Fellowship
  • 财政年份:
    2020
  • 资助国家:
    英国
  • 起止时间:
    2020 至 无数据
  • 项目状态:
    已结题

项目摘要

Circadian rhythms are thought to control many biological pathways, yet its role in disease is only now beginning to be explored. At the heart of the circadian rhythm are clock proteins which oscillate over 24 hours. In our studies concerning circadian rhythms, we have recently made two exciting findings. Firstly, we have discovered that the incurable human disease, pulmonary fibrosis, results in an augmented circadian rhythm. This allows clock proteins to play a key role in disease pathogenesis. One of these proteins, called REVERBalpha, affects fibroblasts, a key cell type in fibrosis. Removing REVERBalpha promotes fibroblasts turning into myofibroblasts, which then results in scarring of the lung. This explains why getting rid of REVERBalpha promotes the formation of fibrosis. It also explains why factors that disrupt the circadian clock e.g. sleep duration, shift work and chronotype are associated with the development of fibrosis. This protein can be targeted with chemical compounds, and indeed use of these compounds inhibits scar formation in human fibrotic lung tissue, making it a viable drug target. The second finding concerned the role of circadian rhythms in infection. We have now discovered that this is due to altered macrophage engulfment of bacteria regulated by the clock protein BMAL1, potentially explaining why susceptibility to infection is time-of-day dependent.I now plan to investigate the consequences of infection in pulmonary fibrosis, focusing on whether the time-of-day variability is increased. Initially we will use a model of fibrosis to investigate what times of day you are more likely to get an infection. We then plan to stop the circadian clock to investigate what proportion of these effects are due to this molecular mechanism.To find out how the circadian clock might exert its effects we plan to study macrophages cultured with sliced lung tissue. Using special microscopes we are able to identify circadian oscillations in real-time allowing us to investigate how these alter engulfment of bacteria. We can then interfere with known fibrotic mediators to see if these factors are driving the increase in circadian oscillation. We now believe that you can also define circadian mechanisms by studying individual single cells. We will aim to assign each cell a specific clock time and then study these cells to see how they change at different phases of the clock. This will mean for the first time that we can gain circadian information from one blood or biological sample, which will be an invaluable tool for circadian biology.
昼夜节律被认为控制着许多生物途径,然而它在疾病中的作用现在才开始被探索。昼夜节律的核心是时钟蛋白质,它们在24小时内振荡。在我们关于昼夜节律的研究中,我们最近有了两个令人兴奋的发现。首先,我们发现,人类不治之症--肺纤维化--会导致昼夜节律增强。这使得时钟蛋白在疾病发病机制中发挥关键作用。其中一种名为REVERBalpha的蛋白质影响成纤维细胞,成纤维细胞是纤维化的一种关键细胞类型。去除REVERBalpha会促进成纤维细胞转化为肌成纤维细胞,从而导致肺部瘢痕形成。这就解释了为什么去除REVERBalpha会促进纤维化的形成。这也解释了为什么打乱生物钟的因素,如睡眠时间、轮班工作和时型与纤维化的发展有关。这种蛋白质可以与化合物靶向,使用这些化合物确实可以抑制人类纤维化肺组织中疤痕的形成,使其成为一个可行的药物靶点。第二个发现涉及昼夜节律在感染中的作用。我们现在已经发现,这是由于巨噬细胞吞噬了由时钟蛋白BMAL1调节的细菌,这可能解释了为什么感染的易感性与每天的时间有关。我现在计划调查感染在肺纤维化中的后果,重点是每天的时间变异性是否增加。首先,我们将使用纤维化模型来调查您在一天中的哪些时间更有可能感染。然后,我们计划停止生物钟,以调查这些影响中有多大比例是由这种分子机制造成的。为了找出生物钟如何发挥其影响,我们计划研究与肺组织切片培养的巨噬细胞。使用特殊的显微镜,我们能够实时识别昼夜节律振荡,使我们能够研究这些变化如何改变细菌的吞噬。然后,我们可以干扰已知的纤维化介质,看看这些因素是否正在推动昼夜振荡的增加。我们现在相信,你也可以通过研究单个单细胞来定义昼夜节律机制。我们的目标是为每个细胞分配一个特定的时钟时间,然后研究这些细胞,看看它们在时钟的不同阶段如何变化。这将意味着我们第一次可以从一个血液或生物样本中获得昼夜节律信息,这将是昼夜生物学的一个无价工具。

项目成果

期刊论文数量(10)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
The UIP honeycomb airway cells are the site of mucin biogenesis with deranged cilia
  • DOI:
    10.1101/2022.09.03.506451
  • 发表时间:
    2022-09
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Jeremy A. Herrera;Lewis A. Dingle;M. Montero;R. Venkateswaran;J. Blaikley;F. Granato;S. Pearson;C. Lawless;D. Thornton
  • 通讯作者:
    Jeremy A. Herrera;Lewis A. Dingle;M. Montero;R. Venkateswaran;J. Blaikley;F. Granato;S. Pearson;C. Lawless;D. Thornton
The UIP/IPF fibroblastic focus is a collagen biosynthesis factory embedded in a distinct extracellular matrix.
UIP/IPF成纤维细胞焦点是嵌合在不同细胞外基质中的胶原蛋白生物合成工厂。
  • DOI:
    10.1172/jci.insight.156115
  • 发表时间:
    2022-08-22
  • 期刊:
  • 影响因子:
    8
  • 作者:
    Herrera, Jeremy A.;Dingle, Lewis;Montero, M. Angeles;Venkateswaran, Rajamiyer V.;Blaikley, John F.;Lawless, Craig;Schwartz, Martin A.
  • 通讯作者:
    Schwartz, Martin A.
Circadian regulation of pulmonary disease: the importance of timing.
Associations of sleep duration and sleep-wake rhythm with lung parenchymal abnormalities on computed tomography: The MESA study.
  • DOI:
    10.1111/jsr.13475
  • 发表时间:
    2022-04
  • 期刊:
  • 影响因子:
    4.4
  • 作者:
    Kim JS;Dashti HS;Huang T;Cade BE;Podolanczuk AJ;O'Hearn DJ;Hoffman EA;Wang H;Blaikley J;Barr RG;Redline S
  • 通讯作者:
    Redline S
Morphologically intact airways in lung fibrosis have an abnormal proteome.
  • DOI:
    10.1186/s12931-023-02400-x
  • 发表时间:
    2023-04-01
  • 期刊:
  • 影响因子:
    5.8
  • 作者:
  • 通讯作者:
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John Blaikley其他文献

Night Shift Work Increases the Risk of Asthma
夜班工作会增加患哮喘的风险
  • DOI:
  • 发表时间:
    2020
  • 期刊:
  • 影响因子:
    0
  • 作者:
    R. Maidstone;R. Maidstone;R. Maidstone;J. Turner;Céline Vetter;Céline Vetter;Hassan S. Dashti;Hassan S. Dashti;Richa Saxena;Richa Saxena;Scheer Fajl.;Scheer Fajl.;Scheer Fajl.;Steven Shea;Simon D. Kyle;Debbie A. Lawlor;Loudon Asi.;John Blaikley;M. K. Rutter;M. K. Rutter;David W. Ray;David W. Ray;David W. Ray;H. Durrington
  • 通讯作者:
    H. Durrington
37: The Manchester experience of total lymphoid irradiation for chronic rejection post lung transplant
37:在肺移植后慢性排斥反应的曼彻斯特总淋巴辐照的经验
  • DOI:
    10.1016/s0167-8140(24)00799-0
  • 发表时间:
    2024-05-01
  • 期刊:
  • 影响因子:
    5.300
  • 作者:
    Sadia Ahmed;Margaret Harris;Karthik Santhanakrishnan;Rajamiyer Venkateswaran;John Blaikley
  • 通讯作者:
    John Blaikley

John Blaikley的其他文献

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{{ truncateString('John Blaikley', 18)}}的其他基金

Investigation of REVERBalpha as a therapeutic target in pulmonary fibrosis
REVERBalpha 作为肺纤维化治疗靶点的研究
  • 批准号:
    MR/L006499/1
  • 财政年份:
    2014
  • 资助金额:
    $ 39.92万
  • 项目类别:
    Fellowship
Glucocorticoid regulation of interleukin 8 expression in chronic obstructive pulmonary disease
糖皮质激素对慢性阻塞性肺疾病白细胞介素8表达的调节
  • 批准号:
    G0601556/1
  • 财政年份:
    2007
  • 资助金额:
    $ 39.92万
  • 项目类别:
    Fellowship

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Baryogenesis, Dark Matter and Nanohertz Gravitational Waves from a Dark Supercooled Phase Transition
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