Type I Interferon Dysregulation in Down Syndrome

唐氏综合症中的 I 型干扰素失调

• 批准号: 9893213
• 负责人: Dusan Bogunovic
• 金额: $ 320.79万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-16 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9893213
• 关键词: Affect; Antiviral Agents; Antiviral Response; Astrocytes; Autoimmune Diseases of the Nervous System; Autoimmune Process; Autoimmunity; Basal Ganglia; Biological Assay; Biology; Blood; Cardiac; Cell Line; Cells; Child; Chromosomes, Human, Pair 21; Clinical; Cognitive; Cognitive deficits; Communicable Diseases; Defect; Disease; Down Syndrome; Fibroblasts; Functional disorder; Gene Dosage; Genes; Genetic; Genetic Transcription; Genotype; Health; Human; IFNAR1 gene; IFNAR2 gene; Immune; Immunity; Immunologics; Immunophenotyping; In Vitro; Individual; Inflammation; Inflammatory; Intellectual functioning disability; Interferon Type I; Interferons; Lead; Measures; Mediating; Microglia; Molecular; Neurodevelopmental Problem; Neurologic; Neurons; Pathogenesis; Pathologic; Pathology; Pathway interactions; Patients; Phagocytosis; Phosphotransferases; Play; Predisposition; Regulation; Series; Signal Transduction; Skin; Specificity; Synaptosomes; Technology; Testing; Textbooks; Therapeutic; autosome; calcification; cell type; cytokine; gastrointestinal; in vivo; induced pluripotent stem cell; inhibitor/antagonist; innovation; insight; nerve stem cell; peripheral blood; pseudotoxoplasmosis syndrome; receptor; response; single-cell RNA sequencing; trafficking; transcription factor; type I interferon receptor; young adult

Project Summary Type I interferons (IFN-Is) are potent cytokines, playing a key role in the antiviral response. However, they can also be detrimental to human health. Type I interferonpathies are disorders known to be caused by IFN-I dysregulation. Mendelian type I interferonopathies, such as Aicardi–Goutières syndrome (AGS), illustrate how the dysregulation of IFN activity can lead to neurological and autoimmune diseases. Down syndrome (DS) is the most common genetic cause of intellectual and developmental disabilities in children and young adults, affecting over 200,000 individuals in the US. In addition to cognitive problems, individuals with DS often have cardiac and gastrointestinal abnormalities. They also have various immunity- related defects, ranging from increased susceptibility to an array of infectious diseases to autoimmunity. Unfortunately, the exact molecular mechanism underlying these immune defects has yet to be elucidated. In most cases, DS is caused by the presence of an extra chromosome 21. Interestingly, the 200 or so genes present on this autosome include those encoding the type I interferon receptors (IFNAR1 and IFNAR2), suggesting a possible effect of gene dosage. Given that some type I interferonopathies are driven by minute increases in the levels of IFN-I cytokines, we decided to investigate the regulation of IFN-I in individuals with DS. This proposal is built around the hypothesis that the relative levels of IFNAR1 and IFNAR2 are the essential factors controlling the responsiveness to and duration of IFN-I responses in a cell type-specific manner in individuals with DS, thereby contributing to the disease. We plan to test this hypothesis, by studying DS patients in vitro, ex vivo, and in vivo at the molecular, immunological, neurological and clinical levels, to assess the functional effects of the increases in the dosage of these genes on the regulation of the IFN pathway in humans. A deeper understanding of the molecular regulation of IFN-I in DS will provide us with greater insight into the pathophysiology of DS and pave the way for the possible use of inhibitors to alleviate the persistent inflammatory disorders associated with DS.

项目概要 I 型干扰素 (IFN-Is) 是有效的细胞因子，在抗病毒反应中发挥着关键作用。 I 型干扰素病是已知由其引起的疾病。 IFN-I 失调。孟德尔 I 型干扰素病，例如 Aicardi-Goutières 综合征 (AGS)。 干扰素活性失调如何导致神经系统和自身免疫性疾病。 唐氏综合症（DS）是智力和发育障碍最常见的遗传原因 儿童和青少年，影响了美国超过 200,000 人。 患有 DS 的人通常有心脏和胃肠道异常，他们也有各种免疫力。 相关缺陷，从对一系列传染病的易感性增加到自身免疫。 不幸的是，这些免疫缺陷背后的确切分子机制尚未阐明。 在大多数情况下，DS 是由额外的 21 号染色体的存在引起的。 该常染色体上存在的基因包括编码 I 型干扰素受体（IFNAR1 和 IFNAR2）的基因， 考虑到某些 I 型干扰素病是由微小的因素引起的，这表明基因剂量可能产生影响。 由于 IFN-I 细胞因子水平增加，我们决定研究 IFN-I 在患有以下疾病的个体中的调节： DS. 该提议是基于 IFNAR1 和 IFNAR2 的相对水平是的假设。 控制细胞类型特异性的 IFN-I 反应的反应性和持续时间的重要因素 我们计划通过研究来检验这一假设。 DS 患者在体外、离体和体内的分子、免疫学、神经学和临床水平上， 评估增加这些基因剂量对 IFN 调节的功能影响 人类的途径。 更深入地了解 DS 中 IFN-I 的分子调控将为我们提供更深入的见解 DS 的病理生理学，并为可能使用抑制剂来缓解持续性症状铺平了道路 与 DS 相关的炎症性疾病。