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
• 负责人: Szewczuk, Myron
• 金额: $ 2.19万
• 依托单位: Queen's University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2016
• 资助国家: 加拿大
• 起止时间: 2016-01-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=613468
• 关键词: Novel; molecular; signaling; platform; regulating

Molecular-targeted G-protein-coupled receptor (GPCR) signaling in human disease has become an important area to scientific and medical professionals. I am studying GPCR signaling because my research program has discovered an entirely new GPCR signaling platform. The interactions between GPCRs with their large number of different G-protein subunits and glycosylated receptors involved in all cells of our body are quite diverse. A vast array of stimuli is capable of eliciting conformational changes in these receptors. They are activated by many ligands, both internal within the body, such as hormones and neurotransmitters, and external light, odorants, and others. One GPCR is capable of initiating multifunctional signaling which may potentiate an amplification of the response produced by separate circumstantial signals within the cell. This cross-talk among different GPCR transduction signals is a focus of intense research in the world. My HQPs and I have uncovered the invisible link connecting ligand-binding and receptor activation to a novel GPCR-signaling platform. This molecular organizational GPCR-signaling platform potentiates Neu1 sialidase and matrix metalloproteinase-9 (MMP-9) enzyme cross-talk on growth factor and pathogen-sensing TOLL-like receptors (TLRs) to facilitate receptor association and cellular signaling. The process involves ligand binding to receptors to initiate a conformational change to potentiate GPCR-signaling and MMP-9 activation to induce Neu1. Activated Neu1 specifically hydrolyzes a-2,3-sialyl residues on receptors, the structural perturbation of which triggers dimeric receptor complex formation and subsequent activation. Collectively, this evidence supports a new role for Neu1 and MMP9 enzymes in the activation of glycosylated receptors through yet an undefined mechanism(s). The long term objective is to increase our comprehension at the molecular and genetic levels of the new role for the Neu1-MMP9 crosstalk in alliance with a functional GPCR-signaling complex in controlling receptor activation. We are convinced that our study will provide the first demonstration for this new GPCR signaling platform as a potential signal transducing mechanism for receptors in cellular responses to stimuli. Since several cell-expressed GPCRs have been identified and targeted with therapeutic intent in human diseases involving infectious disease to cancer, studies about the key players potentiating GPCR-signaling to activate MMP-9 and Neu1 would radically redefine the current dogma(s) governing the mechanism of the cross talk between GPCR and cellular responses to stimuli. Targeting the molecular GPCR-signaling platform tethered to growth factor and pathogen-sensing receptors may provide important biological approaches to disease-intervention strategies and to benefit Canadians.

分子靶向的G蛋白偶联受体（GPCR）信号转导在人类疾病中的作用已成为科学和医学专业人员的重要领域。我正在研究GPCR信号，因为我的研究项目发现了一个全新的GPCR信号平台。GPCR与其大量不同的G蛋白亚基和糖基化受体之间的相互作用涉及我们身体的所有细胞是相当多样的。大量的刺激能够引起这些受体的构象变化。它们被许多配体激活，包括体内的激素和神经递质，以及外部的光，气味等。一个GPCR能够启动多功能信号传导，这可能增强细胞内由单独的环境信号产生的反应的放大。不同GPCR转导信号之间的这种串扰是世界上激烈研究的焦点。我和我的HQP已经发现了连接配体结合和受体激活到一个新的GPCR信号平台的无形联系。这种分子组织GPCR信号平台增强Neu 1唾液酸酶和基质金属蛋白酶-9（MMP-9）酶对生长因子和病原体敏感TOLL样受体（TLR）的相互作用，以促进受体缔合和细胞信号传导。该过程涉及配体与受体结合以启动构象变化，从而增强GPCR信号传导和MMP-9活化以诱导Neu 1。活化的Neu 1特异性水解受体上的α-2，3-唾液酸残基，其结构扰动触发二聚体受体复合物的形成和随后的活化。总的来说，这些证据支持Neu 1和MMP 9酶通过尚未确定的机制在糖基化受体活化中的新作用。长期目标是增加我们在分子和遗传水平上对Neu 1-MMP 9串扰与功能性GPCR信号传导复合物在控制受体活化中的新作用的理解。我们相信，我们的研究将首次证明这种新的GPCR信号平台是细胞对刺激反应中受体的潜在信号转导机制。由于几种细胞表达的GPCR已被鉴定并靶向治疗人类疾病，包括感染性疾病和癌症，关于增强GPCR信号传导以激活MMP-9和Neu 1的关键参与者的研究将从根本上重新定义目前的教条，这些教条控制GPCR和细胞对刺激的反应之间的串扰机制。靶向与生长因子和病原体感应受体相关的分子GPCR信号平台可能为疾病干预策略提供重要的生物学方法，并使加拿大人受益。