Role of glucocorticoid signalling in stress adaptation

糖皮质激素信号在应激适应中的作用

基本信息

  • 批准号:
    RGPIN-2019-06291
  • 负责人:
  • 金额:
    $ 6.99万
  • 依托单位:
  • 依托单位国家:
    加拿大
  • 项目类别:
    Discovery Grants Program - Individual
  • 财政年份:
    2022
  • 资助国家:
    加拿大
  • 起止时间:
    2022-01-01 至 2023-12-31
  • 项目状态:
    已结题

项目摘要

The development of adaptive strategies to cope with a wide spectrum of stressors is fundamental to the overall fitness of an organism. Key players that orchestrate the stress response in vertebrates are corticosteroids, and their action can be mediated by two receptors, the glucocorticoid receptor (GR) and the mineralocorticoid receptor (MR). These corticosteroid receptors are evolutionarily conserved and are ubiquitously expressed in vertebrates. My research program aims to understand the mechanisms of glucocorticoid action, and the consequences of stress-related glucocorticoid signalling in adapting animals to stress. Despite the well characterized action of GR, almost nothing is known about the physiological role of MR in fish. Therefore, my overarching hypothesis is that MR signalling is essential for stress axis activation and can operate in a complementary fashion with GR in regulating the highly conserved glucocorticoid-mediated stress adaptation. In this 5-year proposal, my goal is to specifically explore the evolutionarily conserved role of MR in the perception and activation of the stress response, as well as the regulation of stress-related behaviour. My lab recently generated the GR and MR knockout mutants in zebrafish using CRISPR/Cas9 mutagenesis. Using these mutants, we will carry out loss of function studies to fully characterize the role of these receptors in modulating the stress coping mechanisms. We have also generated double GR,MR knockouts (MGR) in zebrafish, and these MGR mutants, in combination with my existing GR and MR mutants, will allow my lab to comprehensively determine the conserved action of corticosteroid receptors in mediating the glucocorticoid-related stress responses. The methodology will involve whole animal studies with zebrafish (wildtype and mutants) at various developmental stages, as well as tissue-specific studies, including liver, gill, heart, head kidney, skeletal muscle, and brain. The studies will determine the contribution of the corticosteroid receptor signalling in regulating the energy substrate re-partitioning associated with stress. The results from these studies will provide novel insights on stress coping mechanisms, and specifically the role of MR signalling in mediating the glucocorticoid effect in restoring homeostasis. Furthermore, the new tools, including receptor knockouts, we have generated will provide an ideal environment for training and collaboration, and will facilitate discoveries of novel pathways involved in stress adaptation. The results from this work will have an impact on all areas of fish stress research, including aquaculture and environmental effects monitoring. It will also have translational potential in the biomedical field, as knockout of either GR or MR in mammals is lethal. Finally, this proposal and the results generated will greatly impact our understanding of the evolutionary conserved role of glucocorticoids in mediating stress adaptation.
适应策略的发展,以应付广泛的压力源是一个有机体的整体适应性的基础。在脊椎动物中,协调应激反应的关键角色是皮质类固醇,它们的作用可以由两种受体介导,糖皮质激素受体(GR)和矿皮质激素受体(MR)。这些皮质类固醇受体在进化上是保守的,在脊椎动物中普遍表达。我的研究项目旨在了解糖皮质激素的作用机制,以及应激相关的糖皮质激素信号在动物适应应激中的作用。尽管GR的作用已被很好地描述,但人们对GR在鱼类中的生理作用几乎一无所知。因此,我的总体假设是MR信号对于应激轴激活至关重要,并且可以与GR互补方式调节高度保守的糖皮质激素介导的应激适应。在这个为期5年的提案中,我的目标是专门探索MR在应激反应的感知和激活以及应激相关行为的调节中的进化保守作用。我的实验室最近使用CRISPR/Cas9诱变技术在斑马鱼中产生了GR和MR敲除突变体。利用这些突变体,我们将进行功能丧失研究,以充分表征这些受体在调节应激应对机制中的作用。我们还在斑马鱼中产生了双GR,MR敲除(MGR),这些MGR突变体,结合我现有的GR和MR突变体,将使我的实验室能够全面确定皮质类固醇受体在介导糖皮质激素相关应激反应中的保守作用。该方法将涉及斑马鱼(野生型和突变型)在不同发育阶段的全动物研究,以及组织特异性研究,包括肝脏、鳃、心脏、头肾、骨骼肌和大脑。这些研究将确定皮质类固醇受体信号在调节与应激相关的能量底物重新分配中的作用。这些研究的结果将为应激应对机制提供新的见解,特别是MR信号在调节糖皮质激素在恢复体内平衡中的作用。此外,包括受体敲除在内的新工具将为培训和合作提供理想的环境,并将促进发现涉及压力适应的新途径。这项工作的结果将对鱼类应激研究的所有领域产生影响,包括水产养殖和环境影响监测。它在生物医学领域也具有转化潜力,因为在哺乳动物中敲除GR或MR都是致命的。最后,这一建议和结果将极大地影响我们对糖皮质激素在调节应激适应中的进化保守作用的理解。

项目成果

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Vijayan, Mathilakath其他文献

Vijayan, Mathilakath的其他文献

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{{ truncateString('Vijayan, Mathilakath', 18)}}的其他基金

Environmental Physiology and Toxicology
环境生理学和毒理学
  • 批准号:
    CRC-2018-00233
  • 财政年份:
    2022
  • 资助金额:
    $ 6.99万
  • 项目类别:
    Canada Research Chairs
Role of glucocorticoid signalling in stress adaptation
糖皮质激素信号在应激适应中的作用
  • 批准号:
    RGPIN-2019-06291
  • 财政年份:
    2021
  • 资助金额:
    $ 6.99万
  • 项目类别:
    Discovery Grants Program - Individual
Total suspended solids impact on native fish species in the Bow River
总悬浮固体对弓河本地鱼类的影响
  • 批准号:
    558259-2020
  • 财政年份:
    2021
  • 资助金额:
    $ 6.99万
  • 项目类别:
    Alliance Grants
Environmental Physiology And Toxicology
环境生理学和毒理学
  • 批准号:
    CRC-2018-00233
  • 财政年份:
    2021
  • 资助金额:
    $ 6.99万
  • 项目类别:
    Canada Research Chairs
Total suspended solids impact on native fish species in the Bow River
总悬浮固体对弓河本地鱼类的影响
  • 批准号:
    558259-2020
  • 财政年份:
    2020
  • 资助金额:
    $ 6.99万
  • 项目类别:
    Alliance Grants
Environmental Physiology and Toxicology
环境生理学和毒理学
  • 批准号:
    CRC-2018-00233
  • 财政年份:
    2020
  • 资助金额:
    $ 6.99万
  • 项目类别:
    Canada Research Chairs
Role of glucocorticoid signalling in stress adaptation
糖皮质激素信号在应激适应中的作用
  • 批准号:
    RGPIN-2019-06291
  • 财政年份:
    2020
  • 资助金额:
    $ 6.99万
  • 项目类别:
    Discovery Grants Program - Individual
Role of glucocorticoid signalling in stress adaptation
糖皮质激素信号在应激适应中的作用
  • 批准号:
    RGPIN-2019-06291
  • 财政年份:
    2019
  • 资助金额:
    $ 6.99万
  • 项目类别:
    Discovery Grants Program - Individual
State-of-the-art biological nanoparticle tracking instrument for interdisciplinary use
最先进的跨学科生物纳米粒子追踪仪器
  • 批准号:
    RTI-2020-00372
  • 财政年份:
    2019
  • 资助金额:
    $ 6.99万
  • 项目类别:
    Research Tools and Instruments
Environmental Physiology and Toxicology
环境生理学和毒理学
  • 批准号:
    CRC-2018-00233
  • 财政年份:
    2019
  • 资助金额:
    $ 6.99万
  • 项目类别:
    Canada Research Chairs

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Role of glucocorticoid signalling in stress adaptation
糖皮质激素信号在应激适应中的作用
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  • 财政年份:
    2021
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    $ 6.99万
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