Transcriptional and non-transcriptional functions of IRF3 in ALD

IRF3 在 ALD 中的转录和非转录功能

• 批准号: 10430300
• 负责人: LAURA E. NAGY
• 金额: $ 16.09万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-05 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10430300
• 关键词: Acceleration; Alcohol abuse; Alcohol consumption; Alcohol-Induced Disorders; Alcoholic Hepatitis; Alcoholic Liver Diseases; Anti-Inflammatory Agents; Antiviral Agents; Antiviral Response; Apoptosis; Apoptotic; BAX gene; Bax protein; Cells; Cessation of life; Chronic; Cirrhosis; Complex; DNA; Data; Development; Double-Stranded RNA; Elements; Ethanol; Exhibits; Failure; Fibrosis; Genes; Genetic Transcription; Hepatic; Hepatitis; Homeostasis; IRF3 gene; Immune; Immune response; Inflammation; Inflammatory; Innate Immune Response; Innate Immune System; Interferons; Knock-in Mouse; Ligands; Liver; Lysine; Mediating; Mitochondria; Molecular; Morbidity - disease rate; Mus; Natural Immunity; Pathogenesis; Pathology; Pathway interactions; Patients; Peripheral; Phenotype; Population; Proteins; Regulation; Reporter; Research Personnel; Resolution; Role; Signal Pathway; Signal Transduction; Stimulator of Interferon Genes; TLR4 gene; Therapeutic Intervention; Tissues; Ubiquitination; Viral Physiology; Virus Diseases; alcohol exposure; alcohol response; cellular targeting; chronic inflammatory disease; ds-DNA; experimental study; hepatocellular injury; improved; injury and repair; liver injury; macrophage; member; microbial; migration; monocyte; mortality; mouse model; novel; prevent; pro-apoptotic protein; receptor; recruit; response; therapeutic target; transcription factor

ABSTRACT Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus-2 (SARS- CoV-2) is a highly contagious and fast-spreading infectious disease, which reached pandemic status in only four months and is spreading worldwide with millions of people being affected. The clinical spectrum of COVID-19 ranges from mild to critically ill diseases. COVID-19 can progress rapidly into acute respiratory distress syndrome (ARDS), multiorgan failure, and even death. In the midst of the COVID-19 epidemic, there is some evidence for increased alcohol purchases. Since people generally buy more alcohol during epidemics, increased alcohol consumption may result in reduced resistance to infections like COVID-19 and promote the progression of the disease. SARS-COV-2 is a positive-sense single stranded RNA (ssRNA). While alcohol consumption has not yet been shown to directly increase risk for SARS-COV-2 transmission or COVID-19 severity, alcohol negatively affects the both the innate and adaptive immune systems and increases risk for many infectious diseases. Importantly, recent data from both murine models of ethanol exposure and peripheral blood mononuclear cells (PBMCs) from patients with alcohol-associated hepatitis (AH) indicate that signaling by viral ss/dsRNA is disrupted by alcohol, analogous to impact of alcohol on signaling via bacterial products, such as LPS. The parent RO-1 (Transcriptional and non-transcriptional roles of IRF3 in ALD) for this URGENT COMPETITIVE RENEWAL, we are investigating the impact of chronic ethanol on ss/ds RNA sensing and activation of IRF3-mediated cellular responses. Here we propose to extend the scope of this RO1 to address two important aspects of the interaction of alcohol and COVID-19 in people consuming alcohol. In Specific Aim 1, making use of data from the UK Biobank, we will ask whether alcohol consumption or alcohol-related diseases increase risk of infection, hospitalization and mortality. In Specific Aim 2, we will use single cell RNA seq analysis to interrogate the impact of alcohol consumption on anti-viral responses in peripheral innate and adaptive immune cells. Understanding the impact of alcohol use on risk for COVID-19 and characterizing the specific cellular changes in anti-viral responses will meet an important unmet clinical need for guiding public health and medical responses to the COVID-19 pandemic.

摘要 由严重急性呼吸道综合征冠状病毒-2（SARS-）引起的2019冠状病毒病（COVID-19） CoV-2）是一种高度传染性和快速传播的传染病，仅在四年内就达到了大流行状态 几个月，并在世界范围内蔓延，数百万人受到影响。2019冠状病毒病的临床谱 从轻微到严重的疾病。COVID-19可迅速发展为急性呼吸窘迫综合征 （ARDS），多器官衰竭，甚至死亡。在COVID-19疫情期间，有一些证据表明， 增加酒精购买。由于人们通常在流行病期间购买更多的酒精， 消费可能导致对COVID-19等感染的抵抗力下降，并促进疾病的进展。 疾病SARS-COV-2是一种正义单链RNA（ssRNA）。虽然酒精消费没有 但已被证明会直接增加SARS-COV-2传播或COVID-19严重程度的风险， 影响先天免疫系统和适应性免疫系统，并增加许多传染病的风险。 重要的是，最近的数据，从小鼠模型的乙醇暴露和外周血单核细胞 酒精相关性肝炎（AH）患者的外周血单个核细胞（PBMC）表明，病毒ss/dsRNA的信号传导是 被酒精破坏，类似于酒精对经由细菌产物（例如LPS）的信号传导的影响。母 RO-1（ALD中IRF 3的转录和非转录作用）， 我们正在研究慢性乙醇对ss/ds RNA传感和IRF 3介导的细胞内信号转导的影响。 应答在此，我们建议扩展此RO 1的范围，以解决交互的两个重要方面 酒精和COVID-19在饮酒人群中的作用。在具体目标1中，利用联合王国的数据 生物银行，我们将询问饮酒或酒精相关疾病是否会增加感染风险， 住院率和死亡率。在具体目标2中，我们将使用单细胞RNA测序分析来询问 饮酒对外周先天性和适应性免疫细胞抗病毒反应的影响。理解 酒精使用对COVID-19风险的影响，并描述抗病毒药物的特定细胞变化 这些反应将满足指导公共卫生和医疗反应的重要未满足的临床需求， 2019冠状病毒病大流行。