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Mechanisms of reversible DUB oxidation in genome stability pathways - Revision

基因组稳定性途径中可逆 DUB 氧化的机制 - 修订版

基本信息

批准号：
10174167
负责人：
Tony Tung Huang
金额：
$ 35.43万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-16 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10174167
关键词：
2019-nCoV Address Adult Respiratory Distress Syndrome Affect Antiviral Agents Arrhythmia Biochemical Biochemistry COVID-19 COVID-19 pandemic Carcinogens Caspase Cell Cycle Regulation Cell physiology Cells Cellular biology Cessation of life Chemicals Civilization Cleaved cell Common Cold Virus Coronavirus Country Coupling Cysteine DNA Repair Data Death Rate Defense Mechanisms Deubiquitinating Enzyme Development Disease Drosophila pros protein Environment Environmental Exposure Environmental Pollution Environmental Risk Factor Enzymes Epithelial Cells Equilibrium Event Family Fatality rate Free Radicals Future Gene Expression Generations Genome Stability Goals Grant Heavy Metals Human ISG15 gene Immune response In Vitro Individual Infection Inhalation Knowledge Lead Life Lung Lung diseases Mass Spectrum Analysis Mediating Middle East Respiratory Syndrome Middle East Respiratory Syndrome Coronavirus Modeling Modernization Molecular Names Oxidants Oxidation-Reduction Oxidative Stress Oxygen Pathogenesis Pathogenicity Pathway interactions Peptide Hydrolases Pesticides Phosphotransferases Poison Population Predisposition Prevalence Proteins Proteome Proteomics Publishing RNA Reactive Oxygen Species Recombinant Proteins Recombinants Regulation Research Research Proposals Respiratory physiology Role SARS coronavirus Series Severe Acute Respiratory Syndrome Severities Source Techniques Testing Therapeutic Ubiquitin Ubiquitin Like Proteins Ubiquitination Viral Virus Diseases base body system cellular targeting cigarette smoke comorbidity environmental agent enzyme activity human coronavirus in vitro activity infection rate interest lysosomal proteins microbial mutant novel novel coronavirus novel therapeutics novel virus oxidation pandemic disease pollutant preference protein degradation response small molecule success targeted treatment toxic metal

项目摘要

PROJECT SUMMARY/ABSTRACT The current pandemic of COVID-19 (Coronavirus Disease-2019), a respiratory disease that has led to over 5 million confirmed cases and over 350,000 fatalities in over 100 countries since its emergence in late 2019, is caused by a novel virus strain, SARS-CoV-2, an enveloped, positive- sense, single-stranded RNA beta-coronavirus of the family Coronaviridae. My lab has a long- standing interest in understanding how cellular DUBs are regulated by environmentally-produced small molecules, including ROS, toxic heavy metals, chemical pollutants and carcinogens. Similar to human DUBs, viral DUBs, such as the coronavirus Plpro, are proteases that cleave ubiquitin or ubiquitin-like proteins from pro-proteins or from conjugates on target proteins. In doing so, viral DUBs hijack the balance of ubiquitination dynamics in infected cells, potentially disrupting numerous cellular functions, including cell cycle regulation, proteasomal and lysosomal protein degradation, gene expression, kinase activation, DNA repair and ultimately favoring microbial pathogenesis. How viral DUBs are particularly susceptible to environmental exposures, such as ROS and chemical pollutants, have not been adequately explored, especially as novel modulators of human pathogenesis. As it pertains to the rapid global spread of SARS-CoV-2 and the prevalence of COVID-19 disease in the U.S. population and worldwide, we will be focusing our research goals on understanding 1) how the SARS-CoV-2 Plpro protease activity (cleavage of pro-proteins, ubiquitin-, and ISG15-conjugated proteins) can be regulated by environmentally- generated small molecules, and 2) identifying COVID-19 disease-relevant cellular targets of the Plpro upon viral infection in human lung epithelial cells.

项目摘要/摘要目前的新冠肺炎大流行(冠状病毒病-2019年)，这是一种呼吸道疾病，已经自疫情爆发以来，已在100多个国家和地区造成500多万例确诊病例和350,000多人死亡 2019年末出现的SARS-CoV-2是由一种新型病毒株SARS-CoV-2引起的，它是一种包膜的阳性- 冠状病毒科的正义单链RNAβ冠状病毒。我的实验室有一个很长的- 了解环境产生的细胞复制如何受到监管的长期兴趣小分子，包括ROS、有毒重金属、化学污染物和致癌物。类似对于人类来说，病毒副本，如冠状病毒Plpro，是裂解泛素的蛋白酶或来自原蛋白或来自目标蛋白上的结合物的泛素样蛋白。在这样做的过程中，病毒 DUBS劫持了受感染细胞中泛素化动力学的平衡，潜在地扰乱了多种细胞功能，包括细胞周期调节、蛋白酶体和溶酶体蛋白降解、基因表达、激酶激活、DNA修复，最终有利于微生物发病机制。病毒复制如何特别容易受到环境暴露的影响，例如 ROS和化学污染物还没有被充分开发，特别是作为新的调节剂人类的致病机制。因为它与SARS-CoV-2在全球的快速传播和新冠肺炎在美国和世界范围内的流行，我们将把我们的重点放在研究目标1)SARS-CoV-2 PlPro蛋白酶活性(裂解原蛋白、泛素和ISG15结合蛋白)可以由环境- 产生的小分子，以及2)识别与新冠肺炎疾病相关的细胞靶点 PLPro对人肺上皮细胞病毒感染的影响。