Type I Interferon Dysregulation in Down Syndrome

项目摘要 I型干扰素（IFN-1）是一种有效的细胞因子，在抗病毒反应中起着关键作用。然而，在这方面， 它们也可能对人体健康有害。I型干扰素病是已知由以下引起的病症： IFN-I失调。孟德尔I型干扰素病，如Aicardi-Goutières综合征（AGS），说明 干扰素活性失调如何导致神经系统和自身免疫性疾病。 唐氏综合征（DS）是最常见的智力和发育障碍的遗传原因， 儿童和年轻人，影响了美国20多万人。除了认知问题， 患有DS的个体通常具有心脏和胃肠道异常。他们也有各种各样的豁免权- 相关的缺陷，从增加对一系列传染病的易感性到自身免疫。 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。有意思的是， 存在于该常染色体上的基因包括编码I型干扰素受体（IFNAR 1和IFNAR 2）的基因， 这表明基因剂量可能会产生影响。鉴于一些I型干扰素病是由分钟驱动的， IFN-I细胞因子水平的增加，我们决定研究IFN-I在患有以下疾病的个体中的调节： DS.该建议是建立在IFNAR 1和IFNAR 2的相对水平是 控制细胞类型特异性IFN-1应答的应答性和持续时间的重要因素 方式在个人与DS，从而有助于疾病。我们计划通过研究来验证这一假设 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， 评估这些基因剂量增加对IFN-γ调节的功能影响， 人类的道路。 更深入地了解IFN-1在DS中的分子调控将为我们提供更深入的了解， DS的病理生理学，并为可能使用抑制剂来缓解持续性 与DS相关的炎症性疾病。

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.