Role of IRF3 and RXRa Crosstalk in Host Response to Viral Infections

IRF3 和 RXRa 串扰在宿主对病毒感染的反应中的作用

基本信息

批准号：
7687186
负责人：
GENHONG CHENG
金额：
$ 38.5万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-17 至 2009-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7687186
关键词：
Accounting Acetaminophen Acute Liver Failure Adenoviruses Agonist Americas Antiviral Agents Antiviral Response Aspirin Biological Cells Cellular Metabolic Process Chemosensitization Child DNA Viruses Data Disease Gene Targeting Genes Goals Hepatocyte Hepatotoxicity Hormones Host Defense Human IRF3 gene Immune Immune response Infection Influenza Interferon Type I Investigation Knockout Mice Lead Mediating Metabolic Diseases Metabolic Pathway Metabolism Methods Molecular Mus Nuclear Nuclear Hormone Receptors Nuclear Receptor Gene Nuclear Receptors Pathway interactions Patients Pharmaceutical Preparations RNA RXR Receptor Gene Repression Role Signal Pathway Signaling Molecule Syndrome Testing Tissue Transplantation Toll-like receptors Vesicular stomatitis Indiana virus Viral Viral Pathogenesis Virus Virus Diseases cell type gene repression human IRF3 protein immunoregulation interferon regulatory factor-3 mouse model novel novel strategies pathogen prevent programs

项目摘要

The long term goal of this application is to greater elucidate the mechanisms and biological significance of crosstalk between the innate immune response and nuclear hormone receptors in host defense against infections and in pathogen-associated metabolic diseases. Preliminary data in our lab has identified a novel Interferon Regulatory Factor 3(IRF3)-dependent but type I interferon independent pathway induced during innate immune response to viral product stimulation or viral infection, which can lead to strong transcriptional repression of Retinoid X Receptor a (RXRa). As RXRa is the major heterodimer partner for most of the nuclear hormone receptors involved in numerous cellular metabolic processes, we hypothesize that repression of RXRa and its regulated genes during viral infections can contribute to the pathogenesis of viral associated metabolic diseases such as Reye¿s Syndrome, a hepatotoxicity disease that occurs when children are given aspirin in the context of a viral infection. Furthermore, additional preliminary data in our lab showed that nuclear hormone receptor agonists can suppress the induction of antiviral genes and promote viral replications. We therefore also hypothesize that repression of nuclear hormone receptors by the innate immune response may contribute to a proper anti-viral response. In this application, we will determine the roles and mechanisms of the crosstalk between anti-viral immune response and nuclear hormone receptors in both viral associated hepatotoxicity and host defense against viral infections. We plan to first develop mouse models that mimic Reye¿s Syndrome and acetaminophen (APAP)-induced hepatotoxicity. We will then use these mouse models to determine the molecular mechanisms responsible for hepatotoxicity resulting from the crosstalk between anti-viral immune response and nuclear hormone receptors. Finally, we will analyze the effects of nuclear hormone receptors and their agonists on anti-viral innate immune responses to determine if the repression of nuclear hormone receptors by innate immune response is necessary for the proper host defense against viral infections. We believe our investigation of the crosstalk between the innate immune response and nuclear hormone receptor-mediated metabolism will not only help us to understand the mechanisms responsible for viral induced metabolic diseases and drug induced immuno-suppressions but will also provide novel strategies to prevent or treat patients with viral infections and their associated metabolic diseases.

该应用的长期目标是更好地阐明其机制和生物学意义先天免疫反应和核激素受体在宿主防御中的串扰我们实验室的初步数据已经发现了一种新的疾病。干扰素调节因子 3 (IRF3) 依赖性但 I 型干扰素独立途径诱导对病毒产物刺激或病毒感染的先天免疫反应，这可能导致强烈的转录类视黄醇 X 受体 a (RXRa) 的抑制，因为 RXRa 是大多数异二聚体的主要伴侣。核激素受体参与许多细胞代谢过程，我们参与了这种抑制病毒感染期间 RXRa 及其调控基因的表达可能有助于病毒相关疾病的发病机制代谢性疾病，如雷氏病¿ s 综合征，一种儿童服用药物时发生的肝毒性疾病此外，我们实验室的其他初步数据表明，阿司匹林在病毒感染中的作用。核激素受体激动剂可以抑制抗病毒基因的诱导并促进病毒复制。因此，我们还发现先天免疫反应对核激素受体的抑制可能有助于适当的抗病毒反应。在此应用中，我们将确定其作用和机制。两种病毒相关的抗病毒免疫反应和核激素受体之间的串扰我们计划首先开发模仿的小鼠模型。雷耶克然后我们将使用这些小鼠模型。确定导致肝毒性的分子机制最后，我们将分析核激素受体的抗病毒免疫反应。激素受体及其激动剂对抗病毒先天免疫反应的影响，以确定是否抑制先天免疫反应产生的核激素受体对于宿主正确防御病毒是必要的我们相信我们对先天免疫反应和核之间的串扰的研究。激素受体介导的代谢不仅有助于我们了解负责的机制病毒引起的代谢疾病和药物引起的免疫抑制，但也将提供新的策略预防或治疗病毒感染及其相关代谢性疾病的患者。