Regulation of the interferon lamda receptor by influenza

流感对干扰素λ受体的调节

基本信息

批准号：
10456935
负责人：
Rama K Mallampalli
金额：
$ 55.66万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-04-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10456935
关键词：
26S proteasome 3&apos Untranslated Regions Alveolar Macrophages Antiviral Response Area Bacterial Pneumonia Biology Cartoons Cause of Death Cessation of life Critical Illness Data Disease Economic Burden Foundations Genes Genetic Models Genetic Transcription Host Defense Host Defense Mechanism Human Immune response Impairment In Vitro Infection Inflammatory Influenza Injury Interferons Lung Mediating Messenger RNA MicroRNAs Modeling Molecular Mus Pathogenesis Pathway interactions Patients Persons Phase Play Pneumonia Proteins Regulation Resolution Role Signal Transduction Transcript Ubiquitin Ubiquitination United States Up-Regulation Viral Viral Genes Viral Load result Virulent Virus Virus Diseases Virus Receptors Virus Replication antagonist improved in vivo influenza infection influenzavirus inhibitor insight lung injury mRNA Stability mRNA Transcript Degradation macrophage molecular modeling monocyte novel pathogen prevent protein degradation receptor receptor expression response therapeutic target ubiquitin-protein ligase

项目摘要

Influenza is a leading cause of death in the US with a staggering economic burden. Interferons serve as a critical response to this virus triggering elaboration of host defense molecules within alveolar macrophages. A relatively new and unchartered area in interferon biology involves interferon lamda (IFN) acting through its cognate receptor, IFNLR1, to mediate anti-viral defense. Loss of IFNLR1 leads to viral dissemination and death in experimental influenza. The mechanistic platform of this proposal resides on our discovery of a unique molecular model whereby a protein, Fbxo45, rapidly impairs host defense by mediating ubiquitin-driven disposal of this crucial cytoprotective, anti-viral receptor, IFNLR1. Hence, in this application we will first elucidate how short-term influenza infection depletes IFNLR1 through Fbxo45, thereby accentuating experimental viral lung injury (Aim 1). We will specifically elucidate how Fbxo45 targets IFNLR1 for its degradation using complementary in vitro and in vivo genetic models. Next, after sustained influenza infection we observed that IFNLR1 mRNA levels increase in macrophages, perhaps as a compensatory host defense mechanism. Here we will assess novel post-transcriptional mechanisms mediated by microRNA acting on the 3’UTR of the IFNLR1 gene (Aim 2). These studies will provide a new pathobiologic model of lung injury that will serve as a platform for unveiling new molecular insight into the IFN- IFNLR1 axis that is indispensable to resolve inflammatory injury in subjects with severe virally-driven critical illness.

流感是美国的一个主要原因，干扰素带来了惊人的经济负担。作为对该病毒的关键反应，触发宿主防御分子的形成肺泡巨噬细胞是干扰素生物学中一个相对较新且未知的领域。干扰素 lamda (IFN●) 通过其同源受体 IFNLR1 发挥作用，介导抗病毒作用 IFNLR1 的缺失会导致实验性流感病毒传播和死亡。该提案的机制平台在于我们发现了独特的分子模型因此，Fbxo45 蛋白通过介导泛素驱动的处置迅速损害宿主防御因此，在本申请中，我们将首先研究这种重要的细胞保护性抗病毒受体 IFNLR1。阐明短期流感感染如何通过 Fbxo45 消耗 IFNLR1，从而强调实验性病毒性肺损伤（目标 1）。使用互补的体外和体内遗传模型靶向 IFNLR1 的降解。接下来，在持续感染流感后，我们观察到 IFNLR1 mRNA 水平增加巨噬细胞，也许作为一种补偿性宿主防御机制。作用于 3’UTR 的 microRNA 介导的新型转录后机制 IFNLR1 基因（目标 2）。这些研究将提供一种新的肺损伤病理生物学模型。将作为一个平台，揭示 IFN●- IFNLR1 轴的新分子见解对于解决患有严重病毒驱动的危重疾病的受试者的炎症损伤是必不可少的。