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How Non-transcriptional IRF3 Prevents ALD

非转录 IRF3 如何预防 ALD

基本信息

批准号：
9767644
负责人：
Saurabh Chattopadhyay
金额：
$ 18.23万
依托单位：
UNIVERSITY OF TOLEDO HEALTH SCI CAMPUS
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：
2018-09-01 至 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9767644
关键词：
Acute Affect Alcohol consumption Alcoholic Hepatitis Alcoholic Liver Diseases Antiviral Agents Apoptosis Apoptotic Attenuated Biochemical CASP3 gene Cell Death Cells Cessation of life Chronic Cirrhosis Complex Disease Progression Engineering Enterobacteria phage P1 Cre recombinase Ethanol Exhibits Fibrosis Future Gene Expression Genes Genetic Transcription Goals Health Hepatic Hepatocyte Human IRF3 gene Inflammasome Inflammatory Inflammatory Response Investigation Knock-in Mouse Knowledge Kupffer Cells Liver Location LoxP-flanked allele Mediating Microscopic Mitochondria Modeling Molecular Mus Myeloid Cells Pathogenesis Pathogenicity Pathway interactions Pharmacology Physiological Post-Translational Protein Processing Prevention Preventive Production Role Signal Transduction Site TLR4 gene Testing Therapeutic Triglycerides Tumor-infiltrating immune cells Ubiquitination Virus Virus Diseases Work alcohol exposure base cell type cost cytokine feeding genetic approach in vivo knock-down liver injury macrophage monocyte mutant neutrophil p65 prevent preventable death protective effect transcription factor

项目摘要

Project Summary/Abstract Alcoholic liver diseases (ALD) affect over 10 million people in the world and costs more than $150 billion a year in USA. Long-term consumption of alcohol leads to various forms of liver injury including alcoholic hepatitis, fibrosis and cirrhosis, which are major causes of ALD-induced death. Ethanol (EtOH) induces various forms of cell death, which impacts the pathogenesis of ALD. Our preliminary results indicate that non-transcriptional Interferon regulatory factor 3 (Irf3) prevents ALD in mice. The ALD-preventive Irf3 mutant causes hepatocellular apoptosis during EtOH-exposure. Recently, we have uncovered a new Irf3-mediated apoptotic pathway in virus-infected cells. The apoptotic activity of Irf3 is not dependent on its function as a transcription factor. In this pathway, Irf3 is differentially activated to execute its apoptotic activity. Moreover, our preliminary results indicate that non-transcriptional Irf3 interacts with NF-κB signaling to inhibit pro-inflammatory gene expression. This led us to hypothesize that the Irf3-induced apoptotic cell death is related to its ALD-preventive function. To test our hypothesis, we have formulated two specific aims: a) investigate the specific cells in the liver that uses this pathway to prevent ALD and b) determine the biochemical mechanism of non-transcriptional Irf3-mediated apoptosis and inhibition of NF-κB activity. Successful completion of this study will elevate our knowledge on the prevention and treatment options for ALD. Based on our results, future studies will be directed to understand in-depth the molecular mechanism and specific modulators of this pathway to help prevent ALD.

项目总结/摘要酒精性肝病（ALD）影响着世界上超过1000万人，每年花费超过1500亿美元在美国.长期饮酒会导致各种形式的肝损伤，包括酒精性肝炎，纤维化和肝硬化，这是ALD诱导的死亡的主要原因。乙醇（EtOH）诱导各种形式的细胞死亡，影响ALD的发病机制。我们的初步结果表明，非转录干扰素调节因子3（Irf 3）可预防小鼠ALD。预防ALD的Irf 3突变体导致在EtOH暴露期间肝细胞凋亡。最近，我们发现了一个新的Irf 3介导的凋亡，在病毒感染的细胞中。Irf 3的凋亡活性不依赖于其作为转录因子的功能，因子在该途径中，Irf 3被差异激活以执行其凋亡活性。此外，我们的初步结果表明，非转录的Irf 3与NF-κB信号相互作用，抑制促炎基因表情这使我们假设Irf 3诱导的凋亡细胞死亡与其预防ALD有关。功能为了验证我们的假设，我们制定了两个具体的目标：a）研究特定的细胞中，使用该途径预防ALD的肝脏和B）确定非转录的生物化学机制 Irf 3介导的细胞凋亡和NF-κB活性的抑制。成功完成这项研究将提高我们的了解ALD的预防和治疗方案。根据我们的研究结果，未来的研究将旨在深入了解这一途径的分子机制和特定调节剂，以帮助预防ALD。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

IRF3 inhibits nuclear translocation of NF-κB to prevent viral inflammation.

DOI：
10.1073/pnas.2121385119
发表时间：
2022-09-13
期刊：
Proceedings of the National Academy of Sciences of the United States of America
影响因子：
11.1
作者：
通讯作者：

Autophagy in Virus Infection: A Race between Host Immune Response and Viral Antagonism.

DOI：
10.3390/immuno2010012
发表时间：
2022-03
期刊：
Immuno
影响因子：
0
作者：
Chawla K;Subramanian G;Rahman T;Fan S;Chakravarty S;Gujja S;Demchak H;Chakravarti R;Chattopadhyay S
通讯作者：
Chattopadhyay S

Autophagic checks and balances of cellular immune responses.

DOI：
10.1080/27694127.2022.2058677
发表时间：
2022
期刊：
Autophagy reports
影响因子：
0
作者：
通讯作者：

Transcriptional and Non-Transcriptional Activation, Posttranslational Modifications, and Antiviral Functions of Interferon Regulatory Factor 3 and Viral Antagonism by the SARS-Coronavirus.

DOI：
10.3390/v13040575
发表时间：
2021-03-29
期刊：
Viruses
影响因子：
0
作者：
Glanz A;Chakravarty S;Varghese M;Kottapalli A;Fan S;Chakravarti R;Chattopadhyay S
通讯作者：
Chattopadhyay S

Autophagic degradation of IRF3 induced by the small-molecule auranofin inhibits its transcriptional and proapoptotic activities.

DOI：
10.1016/j.jbc.2021.101274
发表时间：
2021-11
期刊：
The Journal of biological chemistry
影响因子：
0
作者：
Glanz A;Chakravarty S;Fan S;Chawla K;Subramanian G;Rahman T;Walters D;Chakravarti R;Chattopadhyay S
通讯作者：
Chattopadhyay S