Type I Interferon Dysregulation in Down Syndrome

项目摘要 I型干扰素是一种强有力的细胞因子，在抗病毒反应中起着关键作用。然而， 它们也可能对人类健康有害。I型干扰素病是已知由 干扰素-I调节失调。孟德尔I型干扰素病，如艾卡迪-古蒂埃综合征(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)是导致智力和发育障碍的最常见的遗传原因 儿童和年轻人，影响到美国20多万人。除了认知问题， DS患者通常有心脏和胃肠道的异常。他们也有各种各样的豁免权- 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是由额外的第21号染色体的存在引起的。有趣的是，大约200人 这个常染色体上存在的基因包括编码I型干扰素受体的基因(IFNAR1和IFNAR2)， 这暗示了基因剂量的可能影响。考虑到某些I型干扰素病是由分钟驱动的 干扰素-I细胞因子水平的增加，我们决定研究干扰素-I在慢性阻塞性肺疾病患者中的调节作用。 DS.这一建议基于这样的假设，即IFNAR1和IFNAR2的相对水平是 控制特定类型细胞对干扰素-I反应的应答和持续时间的基本因素 在DS患者中的方式，从而促成了疾病的发生。我们计划通过研究来检验这一假设 DS患者在体外、体外和体内的分子、免疫学、神经学和临床水平，以 评估这些基因剂量增加对干扰素调节的功能影响 在人类中的途径。 更深入地了解干扰素-I在DS中的分子调控将为我们提供更多的洞察 DS的病理生理机制，并为可能使用抑制剂缓解顽固性 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.