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

理论基础：关于类阿片和大麻素(CB)如何通过G蛋白偶联受体(GPCR)参与宿主代谢的知识空白，加强了了解这些分子的机制作用所需研究的重要性。µ-阿片和大麻素(CB)对宿主代谢和能量平衡的影响的具体机制和细节仍有待阐明。由于加拿大人使用微阿片类药物和CB，这一专题具有很高的相关性；然而，它们与药物副作用和炎性来源的风险因素增加有关。到目前为止，我的NSERC资助的研究发现了一种分子联系，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G蛋白偶联受体(GPCR)信号平台联系起来。GPCRs是感知和传递细胞外刺激的重要通道。因此，它们的多样性和生理重要性使它们成为一种极好的多功能受体。它们可以参与交替的信号通路，这一特性导致了有偏见的GPCR激动症的概念。这个G蛋白信号平台能否预先与生长因子受体酪氨酸激酶(RTK)、病原体敏感的Toll样受体(TLRs)以及µ阿片和CB GPCRs联系在一起？此外，这个偏向的µ-阿片和CB GPCR信号平台能否增强神经氨酸酶-1(Neu1)和基质金属蛋白酶-9(MMP9)在调节RTK和TLR方面的串扰，所有这些都有共同的代谢、疼痛和炎症来源？中心假说：阿片类药物和CB偏向激动剂诱导胰岛素受体IR？亚基，TLR的反式激活是通过神经介素B(NMBR)-Neu1-MMP9在受体糖基化修饰过程中在细胞表面的串扰介导的。研究问题(Q)分为四个部分。问#1：GPCR特异性的µ-阿片和CB激动剂能否介导Neu1-MMP9的串扰，以诱导IR？和TLR受体？问#2：是否存在与MMP9相关的常见GPCR变体，受体配体和GPCRµ-阿片和CB激动剂诱导的Neu1活性？问#3：是否有一个独特的连接物(S)，如Syndecans(Syn-1-4)，脂质连接的Glypcan(Gpc-1-4)或Galectin-3，使GPCr-阿片-和CB-MMP9-Neu1与胰岛素IR？和TLR受体形成复合体。问#4：GPCRµ-阿片类药物和CB-Neu1-MMP9与胰岛素和TLR受体在细胞表面的复合体是否对这些受体的表达是必不可少的？影响和意义：针对阿片类药物和CB受体提出了一种创新和有前途的新信号范式，作为胰岛素和TLR受体的潜在信号转导机制。这些发现的意义将为一种令人兴奋的新出现的机制(S)控制受体信号提供支持。我们将率先探索这一关于这些受体如何相互作用的新想法，并解释健康的加拿大人是如何产生衰弱的药物副作用的。HQP培训：为HQP培训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.