Dissecting the impact of interferon hypersensitivity on mouse models of Down syndrome

项目总结。 21三体(T21)是人类最常见的染色体异常， 引发被称为唐氏综合症(DS)的疾病。DS患者经历一种独特的疾病谱 相对于典型人群，他们受到保护，不受某些条件的影响，如实体癌症和 易患其他疾病，包括阿尔茨海默氏症、血液系统恶性肿瘤和一系列自身免疫性疾病 精神错乱。尽管经过了几十年的研究，DS病理生理学的分子基础仍然不清楚。我们 最近报道，T21导致干扰素(干扰素)反应的结构性激活，可能是由于 Chr21上存在六种干扰素受体中的四种。这个项目的中心假设是过度活跃 干扰素信号参与了DS的病理生理过程。这项提议概述了因果关系 确定干扰素多动与DS相关关系的性质所需的研究 使用干扰素受体三倍体的DS小鼠模型的表型。 目的1.研究免疫刺激对DS表型的影响。使用DS的小鼠模型 随着干扰素受体的三倍增殖，我们将用Dp16来表征对免疫刺激的反应 受体激动剂，聚(I：C)，干扰素α，或干扰素γ，1)这些动物的发育，生长和整体健康，2) 炎性标志物的表达和多种免疫细胞类型的相对丰度，3)炎性标志物 神经炎症和神经变性，以及4)学习、记忆和行为。 目的2.明确IFNR基因剂量对DS表型的贡献。四条21号染色体- 在小鼠中，编码的干扰素受体位于16号染色体上的一个连续簇中。为了测试干扰素的影响 受体拷贝数对免疫敏感性的影响，我们将使Dp16小鼠与我们创造的一个新品系杂交，在该品系中 所有四种干扰素受体都被删除，称为IFNR4KO，以创造出两种(标准化的Dp16)或 IFNR簇的三个(三体)Dp16拷贝。我们还产生了一种节段性复制的菌株 我们将使用它来测试该区域的三倍是否足以驱动DS 表型。 目的3.检测抗干扰素治疗对免疫超敏反应和DS表型的影响。我们会 临床前评估三种独立的ANT-干扰素策略的治疗潜力：1)一种新的JAK1特异性策略 目前正在开发的用于治疗自身免疫性疾病的抑制剂，2)干扰素中和疫苗 正在为HIV相关的神经疾病(手)开发蛋白质，以及3)一种触发 治疗系统性红斑狼疮的干扰素α中和抗体的研制 红斑狼疮(SLE)。

PROJECT SUMMARY. Trisomy 21 (T21) is the most commonly occurring chromosomal abnormality in the human population and gives rise the condition known as Down syndrome (DS). Individuals with DS experience a unique disease spectrum relative to the typical population, whereby they are protected from certain conditions such as solid cancers and predisposed to others including Alzheimer’s Disease, hematopoietic malignancies, and a host of autoimmune disorders. Despite decades of study, the molecular underpinnings of DS pathophysiology remain unclear. We recently reported that T21 results in constitutive activation of the interferon (IFN) response, likely due to the presence of four of the six IFN receptors on chr21. The central hypothesis of this project is that hyperactive IFN signaling contributes to the pathophysiology of DS. This proposal outlines the cause-effect investigations necessary to define the nature of the relationship between IFN hyperactivity and DS-associated phenotypes using mouse models of DS with triplication of the IFN receptors. Aim 1. To characterize the impact of immune stimulation on DS phenotypes. Using a mouse model of DS with triplication of the IFN receptors, termed Dp16, we will characterize the response to immune stimulation with the TLR agonist, poly(I:C), IFNα, or IFNγ, on 1) the development, growth, and overall health of these animals, 2) expression of inflammatory markers and relative abundance of multiple immune cell types, 3) markers of neuroinflammation and neurodegeneration, and 4) learning, memory and behavior. Aim 2. To define the contribution of IFNR gene dosage to DS phenotypes. The four chromosome 21- encoded IFN receptors are located in a contiguous cluster in chromosome 16 in mice. To test the impact of IFN receptor copy number on immune sensitivity, we will cross Dp16 mice to a novel strain we have created in which all four IFN receptors have been deleted, termed IFNR4KO, to create mice with either two (‘normalized’ Dp16) or three (‘trisomic’ Dp16) copies of the IFNR cluster. We have also generated a strain with a segmental duplication of the IFNR cluster, dubbed IFNR3X, which we will use to test if triplication of this region is sufficient to drive DS phenotypes. Aim 3. To test the effect of anti-IFN therapies on immune hypersensitivity and DS phenotypes. We will pre-clinically assess the therapeutic potential of three independent ant-IFN strategies: 1) a novel JAK1-specific inhibitor currently being developed for treatment of autoimmune conditions, 2) an IFN-neutralizing Vaccinia protein being developed for HIV-associated neurological disorder (HAND), and 3) an ‘IFN-kinoid’ that triggers production of IFNα-neutralizing antibodies currently under development for treatment of systemic lupus erythematosus (SLE).