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

原理：我们对微阿片和大麻素（CB）如何通过其G蛋白偶联受体（GPCR）参与宿主代谢的认识存在空白，这加强了了解这些分子的机制作用所需研究的重要性。微阿片和大麻素（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。这个话题是高度相关的，因为加拿大人使用微阿片类药物和CB；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倚G蛋白偶联受体（GPCR）信号传导平台联系起来的分子联系。gpcr是感知和传递细胞外刺激的关键通道。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通路，这一特性导致了偏倚GPCR激动作用的概念。这种g蛋白信号传导平台能否与生长因子受体酪氨酸激酶（RTKs）、病原体感应toll样受体（TLRs）、微阿片样受体和CB gpcr预结合？此外，这种偏倚的µ-阿片类药物和CB GPCR信号传导平台是否可以增强神经氨酸酶-1 （Neu1）和基质金属蛋白酶-9 （MMP9）在调节RTKs和tlr中的串扰，这些RTKs和tlr具有共同的代谢、疼痛和炎症来源？中心假设：µ-阿片类药物和CB偏向性激动剂诱导胰岛素受体IRß亚基，TLR的反激活是通过细胞表面神经介质B (NMBR)-Neu1-MMP9串扰介导的受体糖基化修饰。研究问题(Q)有四个方面。问题1:gpcr特异性µ-阿片样物质和CB激动剂能否介导Neu1-MMP9串扰诱导IRß和TLR受体？问题2：受体配体和GPCR -阿片样物质和CB激动剂诱导的Neu1活性是否需要与MMP9相关的常见GPCR变体？问题3：是否存在一种独特的连接物，如syndecans （Syn-1-4）、脂质连接型glypican （Gpc-1-4）或半凝集素-3，使GPCRµ-opioid-和CB-MMP9-Neu1与胰岛素IRß和TLR受体复合物。问题4:GPCRµ-opioid-和CB-Neu1-MMP-9是否与细胞表面的胰岛素IRß和TLR受体复合物对这些受体的表达至关重要？影响和意义：阿片样物质和CB受体作为胰岛素和TLR受体的潜在信号转导机制，提出了一种创新和有前途的新信号传导范式。这些发现的意义将为控制受体信号的令人兴奋的新出现的机制提供支持。我们将是第一个探索这些受体如何相互作用的新想法，并解释健康的加拿大人如何产生使人衰弱的药物副作用。HQP培训：为HQP培训的顺利完成提供了良好的环境。

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.