Role of SARS-CoV-2-mediated Type I IFN antagonism in individuals with Down Syndrome

SARS-CoV-2 介导的 I 型 IFN 拮抗作用在唐氏综合症患者中的作用

• 批准号: 10158984
• 负责人: Dusan Bogunovic
• 金额: $ 25.59万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10158984
• 关键词: Address; Affect; Antiviral Agents; Autoimmunity; Biology; COVID-19; Cardiac; Cell Line; Cell Nucleus; Cells; Child; Chromosome 21; Clinical Management; Cognitive deficits; Communicable Diseases; Complex; Coronavirus; Country; DNA; Defect; Disease; Disease Management; Dose; Down Syndrome; Epidemic; Fibroblasts; Functional disorder; Gene Dosage; Genes; Genetic; Genetic Transcription; Genotype; Health; Human; IFNAR1 gene; IFNAR2 gene; Immune; Immune system; In Vitro; Incidence; Individual; Infection; Inflammation; Inflammatory; Intellectual functioning disability; Interferon Receptor; Interferon Type I; Interferons; Mediating; Molecular; Nuclear Import; Pathogenesis; Pathology; Pathway interactions; Patients; Phosphorylation; Predisposition; Production; Proteins; Public Health; Regulation; Regulatory Pathway; Role; SARS coronavirus; SH2D3A gene; STAT1 gene; Severe Acute Respiratory Syndrome; Signal Transduction; Skin Abnormalities; Suggestion; System; Trisomy; Viral Physiology; Viral Proteins; Virus; alpha Karyopherins; attenuation; autosome; cytokine; effectiveness measure; gastrointestinal; parent grant; response; type I interferon receptor; viral resistance; virology; young adult

Project Summary Type I Interferons (IFN-Is) are cytokines with potent anti-viral and proinflammatory activities. As such they are tightly regulated to provide enough antiviral effects while not causing over and health disrupting inflammation. Disorders where IFN-Is dysregulation is known to cause pathology are termed type I Interferonopathies. Down syndrome (DS) is the most common genetic cause of intellectual and developmental disabilities in children and young adults with Incidence in US of about 1 in 600 individuals. Individuals with DS often have cardiac and gastrointestinal abnormalities. Additionally, they have a number of immune-related problems from increased susceptibility to an array of infectious diseases to autoimmunity. Unfortunately, the exact molecular mechanism leading to these immune defects has not been elucidated. COVID-19 is a disease caused by a coronavirus, Severe Acute Respiratory Syndrome (SARS) -CoV-2. Infections by SARS-CoV-2 are now present in every country around the globe, causing unprecedented public health burden. SARS-CoV is known to interfere with IFN-I induction and signaling. To which extent SARS-CoV- 2 can cause illness in individuals with DS is currently unknown. DS is, in most cases, caused by an extra chromosome 21, on which the receptors for type I Interferons (IFNAR1 and IFNAR2) are encoded. How this gene dosage effects are contributing to SARS-CoV-2 pathophysiology is not understood. This proposal is built around the hypothesis that relative amounts of IFNAR1 and IFNAR2 are the essential factors controlling SARS- CoV-2 pathophysiology. To address this hypothesis, we propose to study DS patients in vitro at the molecular level to determine the functional significance of dose of these genes in regulating IFN pathway in humans during SARS-CoV-2 infection. Deeper understanding of molecular regulation of IFN-I in DS in the context of SARS-CoV-2 will allow us to better understand how to approach clinical management of disease.

项目摘要 I型干扰素（IFN-1）是具有强效抗病毒和促炎活性的细胞因子。因此他们 受到严格的调节，以提供足够的抗病毒效果，同时不会引起过度和破坏健康的炎症。 其中已知IFN-1 s失调引起病理的病症被称为I型干扰素病。 唐氏综合征（DS）是最常见的智力和发育障碍的遗传原因， 在美国，儿童和年轻人的发病率约为1/600。患有DS的人通常有 心脏和胃肠道异常此外，他们有一些免疫相关的问题， 增加了对一系列传染病的易感性。不幸的是， 导致这些免疫缺陷的机制尚未阐明。 COVID-19是一种由冠状病毒引起的疾病，即严重急性呼吸系统综合征（SARS）-CoV-2。 由SARS-CoV-2引起的感染现在出现在地球仪的每个国家，引起了前所未有的公众关注。 健康负担。已知SARS-CoV会干扰IFN-I的诱导和信号传导。在何种程度上SARS-CoV- 2可能导致疾病的个人与DS目前是未知的。在大多数情况下，DS是由额外的 21号染色体，在其上编码I型干扰素（IFNAR 1和IFNAR 2）的受体。这如何 基因剂量效应对SARS-CoV-2病理生理学的影响尚不清楚。该提案是建立在 围绕IFNAR 1和IFNAR 2的相对量是控制SARS的基本因素这一假设， CoV-2病理生理学。为了解决这一假设，我们建议在体外研究DS患者的分子水平， 水平，以确定这些基因在人类IFN途径调节中的剂量的功能意义。 SARS-CoV-2感染。 深入了解SARS-CoV-2背景下DS中IFN-I的分子调控将使我们能够 更好地了解如何处理疾病的临床管理。