Novel biased G-protein coupled receptor-signalling paradigm regulating growth factor and pathogen-sensing receptors

调节生长因子和病原体感应受体的新型偏向 G 蛋白偶联受体信号传导范式

基本信息

  • 批准号:
    RGPIN-2020-03869
  • 负责人:
  • 金额:
    $ 3.06万
  • 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

Rationale: The gaps in our knowledge regarding how µ-opioid and cannabinoids (CB) are implicated in host metabolism via their G protein-coupled receptors (GPCR) reinforces the importance of research needed to understand the mechanistic action of these molecules. The specific mechanisms and details of the effects of µ-opioid and cannabinoid (CB) on host metabolism and energy homeostasis remain to be elucidated. This topic is highly relevant as µ-opioid and CB are used by Canadians; yet, they have been associated with increased risk factors for drug side effects and inflammatory provenances. My NSERC funded research to date has uncovered a molecular link connecting growth factor-binding receptor activation and immune-mediated inflammation to a novel biased G protein-coupled receptor (GPCR)-signaling platform. GPCRs are critical conduits that sense and communicate extracellular stimuli. Their diversity and physiological importance thus make them superb multifunctional receptors. They can participate in alternate signaling pathways, and this property led to the concept of biased GPCR agonism. Can this G-protein signalling platform pre-associate with growth factor receptor tyrosine kinases (RTKs), pathogen-sensing Toll-like receptors (TLRs) and µ-opioid and CB GPCRs? Also, can this biased µ-opioid and CB GPCR signaling platform potentiate neuraminidase-1 (Neu1) and matrix metalloproteinase-9 (MMP9) crosstalk in regulating RTKs and TLRs, all of which share common metabolic, pain and inflammatory provenances? Central hypothesis: µ-opioid and CB biased agonists-induced insulin receptor IRß subunit, and TLR transactivation is mediated by neuromedin B (NMBR)-Neu1-MMP9 crosstalk on the cell surface in the modification of receptor glycosylation. The research questions (Q) are four-fold. Q#1: Can GPCR-specific µ-opioid and CB agonists mediate Neu1-MMP9 crosstalk to induce IRß and TLR receptors? Q#2: Is there a common GPCR variant linked to MMP9 required for receptor ligand and GPCR µ-opioid and CB agonists-induced Neu1 activity? Q#3: Is there a unique connector(s) such as syndecans (Syn-1-4), lipid-linked glypican (Gpc-1-4) or galectin-3 keeping GPCR µ-opioid- and CB-MMP9-Neu1 in complex with insulin IRß, and TLR receptors. Q#4: Is GPCR µ-opioid- and CB-Neu1-MMP-9 in complex with insulin IRß, and TLR receptors on the cell surface, essential for the expression of these receptors?  Impact and Significance: An innovative and promising new signaling paradigm is proposed for opioids and CB receptors as a potential signal-transducing mechanism for insulin and TLR receptors. The significance of these findings would provide support for an exciting new emerging mechanism(s) for the control of receptor signaling. We will be the first to explore this new idea about how these receptors interact and explain how, otherwise, healthy Canadians develop debilitating drug side effects. HQP Training: Excellent environment for HQP training successful completion.
基本原理:我们关于μ-阿片类药物和大麻素(CB)如何通过其G蛋白偶联受体(GPCR)参与宿主代谢的知识差距加强了了解这些分子的机制作用所需研究的重要性。μ-阿片类药物和大麻素(CB)对宿主代谢和能量稳态影响的具体机制和细节仍有待阐明。这一主题与加拿大人使用的μ-阿片类药物和CB高度相关;然而,它们与药物副作用和炎症来源的风险因素增加有关。迄今为止,我的NSERC资助的研究已经发现了一种将生长因子结合受体激活和免疫介导的炎症与一种新的偏向性G蛋白偶联受体(GPCR)信号平台连接起来的分子联系。GPCR是感知和传递细胞外刺激的重要管道。因此,它们的多样性和生理重要性使它们成为极好的多功能受体。它们可以参与替代信号传导途径,并且这种性质导致了有偏见的GPCR激动作用的概念。 这种G蛋白信号平台能否与生长因子受体酪氨酸激酶(RTK)、病原体敏感Toll样受体(TLR)以及μ-阿片类和CB GPCR预关联?此外,这种偏向性的μ-阿片样物质和CB GPCR信号平台是否可以增强神经氨酸酶-1(Neu 1)和基质金属蛋白酶-9(MMP 9)在调节RTK和TLR时的串扰,所有这些都具有共同的代谢,疼痛和炎症来源?中心假设:μ-阿片类和CB偏向激动剂诱导胰岛素受体IRF 1亚基,TLR反式激活是通过神经介肽B(NMBR)-Neu 1-MMP 9在细胞表面的串扰修饰受体糖基化而介导的。研究问题(Q)有四个方面。Q#1:GPCR特异性μ-阿片和CB激动剂能否介导Neu 1-MMP 9串扰以诱导IR和TLR受体? Q#2:是否存在与MMP 9相关的常见GPCR变体,该变体是受体配体和GPCR μ-阿片类药物和CB激动剂诱导的Neu 1活性所需的?问题三:是否存在独特的连接体,如多配体蛋白聚糖(Syn-1-4)、脂质连接磷脂酰肌醇蛋白聚糖(Gpc-1-4)或半乳糖凝集素-3,使GPCR μ-阿片样物质和CB-MMP 9-Neu 1与胰岛素IRR 4和TLR受体保持复合。问题四:GPCR μ-阿片样物质-和CB-Neu 1-MMP-9与胰岛素受体和细胞表面的TLR受体复合,对这些受体的表达至关重要吗? 影响和意义:阿片类药物和CB受体作为胰岛素和TLR受体的潜在信号转导机制,提出了一个创新的和有前途的新的信号转导模式。这些发现的重要性将为控制受体信号传导的令人兴奋的新机制提供支持。我们将是第一个探索这些受体如何相互作用的新想法,并解释如何,否则,健康的加拿大人发展衰弱的药物副作用。HQP培训:为HQP培训的顺利完成创造良好的环境。

项目成果

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Szewczuk, Myron其他文献

Szewczuk, Myron的其他文献

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{{ truncateString('Szewczuk, Myron', 18)}}的其他基金

Novel biased G-protein coupled receptor-signalling paradigm regulating growth factor and pathogen-sensing receptors
调节生长因子和病原体感应受体的新型偏向 G 蛋白偶联受体信号传导范式
  • 批准号:
    RGPIN-2020-03869
  • 财政年份:
    2021
  • 资助金额:
    $ 3.06万
  • 项目类别:
    Discovery Grants Program - Individual
Mechanism of CoVID-19 induced hyperinflammation
CoVID-19诱导过度炎症的机制
  • 批准号:
    550110-2020
  • 财政年份:
    2020
  • 资助金额:
    $ 3.06万
  • 项目类别:
    Alliance Grants
Novel biased G-protein coupled receptor-signalling paradigm regulating growth factor and pathogen-sensing receptors
调节生长因子和病原体感应受体的新型偏向 G 蛋白偶联受体信号传导范式
  • 批准号:
    RGPIN-2020-03869
  • 财政年份:
    2020
  • 资助金额:
    $ 3.06万
  • 项目类别:
    Discovery Grants Program - Individual
Novel molecular signaling platform regulating receptor activation and cell function
调节受体激活和细胞功能的新型分子信号平台
  • 批准号:
    RGPIN-2015-05301
  • 财政年份:
    2019
  • 资助金额:
    $ 3.06万
  • 项目类别:
    Discovery Grants Program - Individual
Novel molecular signaling platform regulating receptor activation and cell function
调节受体激活和细胞功能的新型分子信号平台
  • 批准号:
    RGPIN-2015-05301
  • 财政年份:
    2018
  • 资助金额:
    $ 3.06万
  • 项目类别:
    Discovery Grants Program - Individual
Novel molecular signaling platform regulating receptor activation and cell function
调节受体激活和细胞功能的新型分子信号平台
  • 批准号:
    RGPIN-2015-05301
  • 财政年份:
    2017
  • 资助金额:
    $ 3.06万
  • 项目类别:
    Discovery Grants Program - Individual
Novel molecular signaling platform regulating receptor activation and cell function
调节受体激活和细胞功能的新型分子信号平台
  • 批准号:
    RGPIN-2015-05301
  • 财政年份:
    2016
  • 资助金额:
    $ 3.06万
  • 项目类别:
    Discovery Grants Program - Individual
Novel molecular signaling platform regulating receptor activation and cell function
调节受体激活和细胞功能的新型分子信号平台
  • 批准号:
    RGPIN-2015-05301
  • 财政年份:
    2015
  • 资助金额:
    $ 3.06万
  • 项目类别:
    Discovery Grants Program - Individual
The role of glycosylation in receptor activation
糖基化在受体激活中的作用
  • 批准号:
    203498-2013
  • 财政年份:
    2013
  • 资助金额:
    $ 3.06万
  • 项目类别:
    Discovery Grants Program - Individual
The role of glycosylation in receptor activation
糖基化在受体激活中的作用
  • 批准号:
    203498-2008
  • 财政年份:
    2012
  • 资助金额:
    $ 3.06万
  • 项目类别:
    Discovery Grants Program - Individual

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Deciphering biased agonistic activation of mu-opioid receptor by novel optogenetic hydrogen peroxide sensor
新型光遗传学过氧化氢传感器破译μ阿片受体的偏向激动激活
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Novel biased G-protein coupled receptor-signalling paradigm regulating growth factor and pathogen-sensing receptors
调节生长因子和病原体感应受体的新型偏向 G 蛋白偶联受体信号传导范式
  • 批准号:
    RGPIN-2020-03869
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Novel Biased Beta2-AR Ligands as Asthma Therapeutics
新型偏向 Beta2-AR 配体作为哮喘治疗药物
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    10581573
  • 财政年份:
    2021
  • 资助金额:
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Novel Biased Beta2-AR Ligands as Asthma Therapeutics
新型偏向 Beta2-AR 配体作为哮喘治疗药物
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    10372196
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    2021
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Novel biased G-protein coupled receptor-signalling paradigm regulating growth factor and pathogen-sensing receptors
调节生长因子和病原体感应受体的新型偏向 G 蛋白偶联受体信号传导范式
  • 批准号:
    RGPIN-2020-03869
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    2020
  • 资助金额:
    $ 3.06万
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    Discovery Grants Program - Individual
Beta-Arrestin-Biased Agonism at the D1 Receptor as a Novel Approach to Levodopa-Induced Dyskinesias in Advanced Parkinson's Disease
D1 受体的 β-抑制蛋白偏向激动是治疗晚期帕金森病中左旋多巴引起的运动障碍的新方法
  • 批准号:
    10022079
  • 财政年份:
    2019
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    $ 3.06万
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Novel mechanism on subpopulation-dependent biased GPCR signaling in neurons
神经元亚群依赖性偏向 GPCR 信号传导的新机制
  • 批准号:
    10174956
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Novel mechanism on subpopulation-dependent biased GPCR signaling in neurons
神经元亚群依赖性偏向 GPCR 信号传导的新机制
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    $ 3.06万
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Novel mechanism on subpopulation-dependent biased GPCR signaling in neurons
神经元亚群依赖性偏向 GPCR 信号传导的新机制
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    10372289
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    2018
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    $ 3.06万
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Novel mechanism on subpopulation-dependent biased GPCR signaling in neurons
神经元亚群依赖性偏向 GPCR 信号传导的新机制
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    9767795
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