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: 2019
• 资助国家: 加拿大
• 起止时间: 2019-01-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=683568
• 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.

人类疾病中的分子靶向 G 蛋白偶联受体 (GPCR) 信号传导已成为科学和医学专业人士的一个重要领域。我正在研究 GPCR 信号传导，因为我的研究项目发现了一个全新的 GPCR 信号传导平台。 GPCR 与其大量不同的 G 蛋白亚基和参与我们身体所有细胞的糖基化受体之间的相互作用是非常多样化的。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，以及外部光、气味剂等。一种 GPCR 能够启动多功能信号传导，从而增强细胞内单独环境信号产生的反应的放大。不同GPCR转导信号之间的串扰是世界范围内研究的热点。我和我的 HQP 发现了配体结合和受体激活与新型 GPCR 信号平台之间的隐形联系。该分子组织 GPCR 信号平台可增强生长因子和病原体感应 TOLL 样受体 (TLR) 上的 Neu1 唾液酸酶和基质金属蛋白酶 9 (MMP-9) 酶的串扰，以促进受体关联和细胞信号传导。该过程涉及配体与受体结合以启动构象变化以增强 GPCR 信号传导和 MMP-9 激活以诱导 Neu1。激活的 Neu1 特异性水解受体上的 a-2,3-唾液酸残基，其结构扰动触发二聚受体复合物的形成和随后的激活。总的来说，这一证据支持 Neu1 和 MMP9 酶通过尚未明确的机制在糖基化受体激活中发挥新作用。长期目标是提高我们在分子和基因水平上对 Neu1-MMP9 串扰与功能性 GPCR 信号复合物在控制受体激活中的新作用的理解。我们相信，我们的研究将为这种新的 GPCR 信号平台作为细胞对刺激做出反应的受体的潜在信号转导机制提供首次证明。由于几种细胞表达的 GPCR 已被鉴定出来，并以治疗人类疾病（涉及传染病和癌症）为目标，因此对增强 GPCR 信号传导以激活 MMP-9 和 Neu1 的关键参与者的研究将从根本上重新定义当前控制 GPCR 与细胞对刺激的反应之间的相互作用机制的教条。针对与生长因子和病原体感应受体相连的分子 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。