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Human ISG15 and USP18 Deficiencies Underlying Type I Interferonopathies

人类 ISG15 和 USP18 缺陷导致 I 型干扰素病

基本信息

批准号：
10581673
负责人：
Dusan Bogunovic
金额：
$ 50.64万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-06-09 至 2027-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10581673
关键词：
2019-nCoV Affect Anti-Inflammatory Agents Antiviral Agents Antiviral Response Antiviral resistance Astrocytes Autoimmune Autoimmune Diseases Blood Cells Cell Line Cell Nucleus Cells Child Clinical Collection Complex DNA Viruses Development Disease Down-Regulation Exposure to Functional disorder Generations Genes Genetic Goals Growth HIV Health Human IFNAR1 gene ISG15 gene Immune response Immunologics In Vitro Individual Infection Inflammation Inflammatory Influenza A virus Influenza B Virus Interferon Type I Interferons Laboratories Lymphoid Tissue Measures Mediating Microglia Molecular Neurologic Neurologic Symptoms Neurons Outcome Pathogenesis Pathogenicity Pathway interactions Patients Phagocytosis Phosphorylation Predisposition Production Property Proteins Proteome RNA RNA Viruses Regulation Resistance Role Sendai virus Signal Transduction Simplexvirus Specificity Spondyloenchondrodysplasia Synaptosomes Testing Therapeutic Agents Tissue Model Tissues Transcription Initiation Ubiquitin Up-Regulation Vesicular stomatitis Indiana virus Viral Virus Virus Diseases Zika Virus antiviral immunity autoinflammatory autoinflammatory diseases autosome calcification cell type cytokine design gene product improved in vivo mutant nerve stem cell nervous system disorder preservation pseudotoxoplasmosis syndrome response transcriptome sequencing type I interferon receptor viral resistance

项目摘要

Project Summary Type I interferons (IFN-Is) have well-documented potent antiviral and inflammatory properties. However, we and others have shown that the inflammatory effects of these cytokines can have detrimental effects on human health. Disorders caused by the prolonged effects of IFN-Is are collectively known as type I interferonopathies. Mendelian type I interferonopathies, such as Aicardi–Goutières syndrome (AGS) and spondyloenchondromatosis (SPENCD) are prime examples of severe neurologic, autoinflammatory and autoimmune diseases caused by the perpetual induction of IFN-Is. We have recently described more than 20 children presenting Mendelian type I interferonopathy. Genetically, we have shown these conditions to be due to complete or partial deficiencies of ISG15 or USP18. These deficiencies affect downregulation of the IFN-I response. Individuals with deficiencies of ISG15 or USP18 have high levels of IFN-I-stimulated gene products in their blood cells, high levels of resistance to viral infections, but also neurologic, autoinflammatory and autoimmune manifestations, akin to those of AGS and SPENCD. This proposal is built around the hypothesis that the pathogenesis of these deficiencies is driven by IFN-I responses in specific tissues, and that these responses could be harnessed in the development of new treatments. We plan to test this hypothesis by studying these deficiencies in vitro, ex vivo, and in vivo at the molecular, immunological, and tissue-specific levels, to determine their functional significance in IFN-I pathway regulation and resistance to viral infections in humans. Improvements in our understanding of the molecular regulation of IFN-I should shed light on the pathophysiology of these deficiencies, paving the way for the development of new treatments for managing persistent inflammatory disorders and enhancing antiviral responses.

项目摘要 I型干扰素（IFN-1）具有有效的抗病毒和炎症特性。然而，在这方面，我们和其他人已经表明，这些细胞因子的炎症效应可能对人体健康由IFN-1长期作用引起的疾病统称为I型干扰素病孟德尔I型干扰素病，如Aicardi-Goutières综合征（AGS）和脊椎软骨瘤病（SPENCD）是严重的神经系统，自身炎症和由IFN-1的永久诱导引起的自身免疫性疾病。我们最近描述了20多名儿童呈现孟德尔I型干扰素病。在遗传学上，我们已经证明这些疾病是由于ISG 15或USP 18的完全或部分缺陷造成的。这些缺陷影响IFN-I应答的下调。缺乏ISG 15或USP 18的个体在他们的血细胞中有高水平的IFN-1刺激的基因产物，对病毒感染有高水平的抵抗力，而且还有神经学、自身炎症和自身免疫表现，类似于AGS和SPENCD的表现。这一个建议是建立在假设这些缺陷的发病机制是由IFN-I反应驱动在特定的组织中，这些反应可以用于开发新的治疗方法。我们计划为了通过在体外、离体和体内在分子，免疫学，和组织特异性水平，以确定其在IFN-1途径调节和抗性中的功能意义人类的病毒感染。我们对IFN-I分子调节的理解的提高应该有助于阐明这些缺陷的病理生理学，为开发新的治疗方法铺平了道路，持续的炎症性疾病和增强抗病毒反应。