Alpha7 Nicotinic Receptor: Structures and Coupling with Intracellular Proteins

Alpha7 烟碱受体：结构及其与细胞内蛋白质的偶联

基本信息

批准号：
10169782
负责人：
PEI TANG
金额：
$ 15.65万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-15 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10169782
关键词：
2019-nCoV Address Administrative Supplement Affect Agonist Animal Model Anosmia Anti-Cholinergics Anti-Inflammatory Agents Authorization documentation Behavior Binding Blood Coagulation Disorders COVID-19 COVID-19 pandemic Cell model Cells Cessation of life Clinical Coupling Disease Electrophysiology (science)Environment Exposure to Foundations Funding Goals Human Infection Inflammation Inflammatory Inflammatory Response Knowledge Lead Length Link Measures Mediating Molecular NMR Spectroscopy National Institute of Drug Abuse Neurosciences Neurotoxins Nicotine Nicotinic Receptors Organ Outcome Outcomes Research Pathway interactions Patients Peptidyl-Dipeptidase A Play Positioning Attribute Process Production Protein C Proteins Research Resources Respiratory Tract Infections Role Sequence Homology Signal Pathway Signal Transduction Snake Venoms Structure Surface Plasmon Resonance Testing Therapeutic Effect Tobacco smoking behavior Transactivation Transfection Up-Regulation Virus Diseases alpha Bungarotoxin alpha-bungarotoxin receptor base combat cytokine cytokine release syndrome design effective therapy experience extracellular macrophage neurotropic outcome forecast prevent protective effect receptor response treatment strategy

项目摘要

The alpha7 nicotinic acetylcholine receptor (α7nAChR) has emerged as a unique player in the infection and progression of COVID-19, which has caused more than 325,000 deaths. α7nAChR links tobacco smoking to major clinical manifestations in COVID-19, including respiratory infection, anosmia, systemic coagulopathy, and cytokine storm. Several sequences of SARS-CoV-2 are found to be homologous to α-bungarotoxin and α- cobratoxin, potent antagonists of α7nAChR. These findings support the hypothesis that SARS-CoV-2 interacts directly with α7nAChR, inhibits its function, and consequently dysregulates the inflammatory responses mediated by α7nAChR. The experimental evidence is urgently needed to correctly establish the role of α7nAChR in COVID-19 and to understand nicotine’s detrimental or protective effects on the onset and progression of COVID- 19. With permission from the NIDA (Dr. Roger Little, Deputy Director, Division of Neuroscience and Behavior), we seek Administrative Supplement support to address several key questions about the involvement of nicotine and α7nAChR in COVID-19. Specifically, we propose to elucidate: (1) where and how SARS-CoV-2 proteins interact with α7nAChR and how nicotine alters such interactions; and (2) how SARS-CoV-2 proteins affect intracellular signaling pathways downstream of α7nAChR that lead to upregulation and transactivation of pro- inflammatory cytokines, and how nicotine modulates the outcome of this process. Considering the widespread expression of α7nAChR in various organs and the significant regulatory role of α7nAChR in the cholinergic anti- inflammatory pathway, our research outcomes can potentially lead to new treatment strategies to combat COVID-19.

α7烟碱乙酰胆碱受体（α7NACHR）已成为感染中的独特 Covid-19的进展已导致325,000多人死亡。 Covid-19，包括呼吸道感染，厌食，全身性凝血病的主要临床表现 SARS-COV-2的细胞因子风暴序列与α-bungarotoxin和α-同源 cobratoxin，α7NACHR的有效拮抗剂。直接使用α7NACHR，抑制是功能，并使炎症反应的炎症失调通过α7nachr，迫切需要经验证据正确地确定α7nACHR的作用 COVID-19，并了解尼古丁对互相进展的有害或保护作用 19。在NIDA的许可下（神经科学与行为部副主任Roger Little博士），我们寻求行政专有人支持，以解决有关尼古丁涉及的严重性和α7nACHR在19.29中，我们建议阐明：（1）SARS-COV-2蛋白如何与α7NACHR相互作用，尼古丁如何改变； α7NACHR下游的细胞内信号通路，导致促进的上调和反式激活综合了广泛。 α7NACHR在各种器官中的表达以及α7nACHR在胆碱能抗抗菌中的重要作用炎症途径，我们的研究成果可以强劲地导致新的治疗策略来对抗新冠肺炎。