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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：
10158443
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/10158443
关键词：
Address Anti-Infective Agents Anti-Inflammatory Agents Antiviral Agents Antiviral Response Autoimmune Autoimmune Diseases of the Nervous System Blood Cells Cell Line Cell Nucleus Cells Child Clinical Collection Complex Computer software Crystallization DNA Viruses Development Disease Exhibits Exposure to Functional disorder Gene Expression Profile Genes Genetic Genetic Transcription Goals Growth Health Human IFNAR1 gene ISG15 gene Immune response Immunologics In Vitro Individual Infection Inflammation Inflammatory Infrastructure 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 Resistance Roentgen Rays Role STAT1 gene STAT2 gene Signal Transduction Specificity Spondyloenchondrodysplasia 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 silico in vivo inhibitor/antagonist mutant negative affect preservation 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.

项目概要 I 型干扰素 (IFN) 是具有明确抗病毒活性的细胞因子。虽然有益效果干扰素有据可查，很明显干扰素对人类也有深远的有害影响健康。干扰素失调引起病理的疾病统称为 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) 展示了 IFN 活性的组成性上调如何导致神经系统和自身免疫性疾病病理学。我们最近发现了 11 名患有孟德尔 I 型干扰素病的儿童。从遗传学上来说，我们发现 6 名儿童完全缺乏 ISG15，5 名儿童完全缺乏 USP18 不足。这些缺陷是影响干扰素负调节的首要遗传缺陷回复。 ISG15 和 USP18 缺陷个体的血液中 IFN 刺激基因升高细胞，对病毒感染的抵抗力增强，而且还具有神经系统和自身免疫表现，类似到 AGS 和 SPENCD。该提案基于这样的假设：ISG15 和 USP18 是必不可少的控制 I 型干扰素反应的反应性和持续时间的因素。为了解决这个假设，我们提议对这 11 名罕见患者进行分子、免疫学和体内研究临床水平以确定这些基因在调节 IFN 通路和耐药性中的功能意义导致人类病毒感染。更深入地了解 IFN 的分子调控将使我们更好地了解这些缺陷背后的病理生理学，将为开发辅助药物奠定基础管理持续性炎症性疾病和/或增加抗病毒反应。