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.

抽象的 冠状病毒病2019（COVID-19）由严重的急性呼吸综合征冠状病毒2（SARS- COV-2）是一种高度传染性且快速传播的传染病，仅在四个中达到了大流行状态 几个月，在全球范围内传播，数百万的人受到影响。 COVID-19的临床光谱 从轻度到严重的疾病范围。 COVID-19可以迅速发展为急性呼吸窘迫综合征 （ARDS），多器官失败甚至死亡。在Covid-19-19的流行病中，有一些证据表明 增加酒精的购买。由于人们在流行期间通常会购买更多的酒精，因此酒精增加 消费可能会导致对诸如Covid-19之类的感染的抵抗力降低，并促进 疾病。 SARS-COV-2是一个正义的单链RNA（SSRNA）。虽然饮酒尚未 但已证明可以直接增加SARS-COV-2传播或共证的严重程度，酒精造成负面影响的风险 影响先天和适应性免疫系统，并增加许多传染病的风险。 重要的是，来自乙醇暴露和外周血单核细胞的鼠模型的最新数据 （PBMC）来自酒精相关肝炎（AH）的患者表明，病毒SS/DSRNA的信号传导为 被酒精破坏，类似于酒精对通过细菌产物（例如LPS）的信号传导的影响。父母 RO-1（IRF3在ALD中的转录和非转录角色）用于这种紧急竞争续约， 我们正在研究慢性乙醇对SS/DS RNA感应和IRF3介导的细胞激活的影响 回答。在这里，我们建议扩展此RO1的范围，以解决交互的两个重要方面 饮酒的人的酒精和库维德。在特定目标1中，利用英国的数据 生物库，我们将询问饮酒或与酒精有关的疾病是否增加感染风险， 住院和死亡率。在特定目标2中，我们将使用单细胞RNA SEQ分析来询问影响 饮酒对外周先天和适应性免疫细胞中抗病毒反应的饮酒。理解 酒精使用对19009的风险的影响并表征抗病毒的特定细胞变化 回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。