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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：
9382702
负责人：
Dusan Bogunovic
金额：
$ 42.38万
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 2022-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9382702
关键词：
Address Anti-Infective Agents Anti-Inflammatory Agents Anti-inflammatory Antiviral Response Autoimmune Diseases of the Nervous System Autoimmune Process Blood Cells Cell Line Cell Nucleus Cells Child Clinical Collection Complex Computer Simulation Computer software Crystallization DNA Viruses Development Disease Exhibits Functional disorder Genes Genetic Genetic Transcription Goals Growth Health Human IFNAR1 gene ISG15 gene Immune response Immunologics In Vitro Individual Infection Inflammation Inflammatory Interferon Receptor Interferon Type I Interferons Knowledge Laboratories Lead Lymphoid Tissue Measures Mediating Medicine Molecular Mutation Neurologic Neurologic Symptoms Outcome Pathogenicity Pathology Pathway interactions Patients Phosphorylation Proteins Proteome RNA Viruses Regulation Research Infrastructure Resistance Roentgen Rays Role STAT1 gene STAT2 gene Signal Transduction Specificity Structure Supercomputing Testing Therapeutic Tissue Model Ubiquitin Up-Regulation Viral Physiology Virus Virus Diseases Zika Virus antiviral immunity cell type cytokine design efficacy testing epigenetic regulation gene induction improved in vivo inhibitor/antagonist mutant negative affect pseudotoxoplasmosis syndrome response small molecule viral resistance

项目摘要

Project Summary Type I Interferons (IFNs) are cytokines with well-defined anti-viral activities. While beneficial effects of IFNs are well documented, it has become clear that IFNs also have profound detrimental effects to human health. Disorders where dysregulated IFNs cause pathology are collectively termed type I Interferonopathies. Mendelian type I Interferonopathy disorders like Aicardi–Goutières syndrome (AGS) and spondyloenchondromatosis (SPENCD) showcase how constitutive upregulation of IFN activity can lead to neurologic and autoimmune disease pathology. We have recently identified eleven children presenting with Mendelian type I Interferonopathy. Genetically, we discovered six children with complete ISG15 deficiency and five children with complete USP18 deficiency. These deficiencies are the first genetic defects affecting the negative regulation of the IFN response. ISG15 and USP18 deficient individuals present with elevated IFN stimulated genes in their blood cells, increased resistance to viral infections, but also with neurologic and autoimmune manifestations, similar to AGS and SPENCD. This proposal is built around the hypothesis that ISG15 and USP18 are the essential factors controlling responsiveness to and duration of type I IFN responses. To address this hypothesis we propose to study these eleven rare patients in vitro, ex vivo, and in vivo at the molecular, immunological, and clinical levels to determine the functional significance of these genes in regulating IFN pathway and resistance to viral infections in humans. Deeper understanding of molecular regulation of IFN will allow us to better understand the pathophysiology behind these deficiencies and will lay the ground for development of medicines aiding management of persistent inflammatory disorders and/or increased anti-viral responses.

项目摘要 I型干扰素(IFN)是具有明确抗病毒活性的细胞因子。虽然这样做的好处 IFN有很好的记录，但很明显，IFN对人类也有深远的有害影响健康。调节失调的干扰素引起的疾病统称为I型干扰素病。孟德尔I型干扰素病，如艾卡迪-古蒂埃综合征(AGS)和脊柱软骨瘤病(SPENCD)展示了干扰素活性的结构性上调如何导致神经学和自身免疫性疾病病理学。我们最近发现有11名儿童患有孟德尔I型干扰素病。在遗传学上，我们发现6名儿童完全缺乏ISG15，5名儿童完全缺乏USP18 缺乏症。这些缺陷是影响干扰素负调控的第一个基因缺陷。回应。ISG15和USP18缺陷者血液中干扰素刺激基因水平升高细胞，对病毒感染的抵抗力增强，但也有神经系统和自身免疫的表现，类似致AGS和SPENCD。这一建议建立在ISG15和USP18是基本的假设之上控制I型干扰素应答和持续时间的因素。为了解决这一假设，我们建议从分子、免疫学、体内外等方面对这11例罕见患者进行研究。临床水平确定这些基因在调节干扰素途径和耐药性中的功能意义人类中的病毒感染。深入了解干扰素的分子调控将使我们更好地理解这些缺陷背后的病理生理学，并将为开发有助于持续炎症性疾病的管理和/或增加的抗病毒反应。