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

剖析干扰素超敏反应对唐氏综合症小鼠模型的影响

• 批准号: 10405551
• 负责人: Kelly D. Sullivan
• 金额: $ 38.41万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10405551
• 关键词: Agonist; Alzheimer' s Disease; Animal Model; Animals; Ants; Autoimmune Diseases; Behavior; Birth; CRISPR/Cas technology; Catabolism; Cells; Characteristics; Chromosome 16; Chromosome 21; Chromosome abnormality; Clinical; Clinical Trials; Data; Development; Disease; Down Syndrome; Dysmorphology; Environment; Frequencies; Functional disorder; Future; Gene Activation; Gene Cluster; Gene Dosage; Genes; Genetic Diseases; Growth; Health; Hematopoietic Neoplasms; Human; Human Chromosomes; Hyperactivity; Hypersensitivity; Immune; Immune system; Immunization; Impairment; Individual; Inflammatory; Interferon Activation; Interferon Type II; Interferon-alpha; Interferons; Investigation; JAK1 gene; Knockout Mice; Kynurenine; Learning; Ligands; Link; Lymphoid; Malignant Neoplasms; Memory; Modeling; Molecular; Mus; Myelogenous; Nature; Nerve Degeneration; Outcome; Pathogenesis; Pathway interactions; Persons; Pharmacology; Phenotype; Plasma; Poly I-C; Population; Preclinical Testing; Process; Production; Proteins; Proteomics; Quinolinic Acid; Receptor Activation; Receptor Gene; Reporting; Role; Severities; Signal Transduction; Solid; Systemic Lupus Erythematosus; Testing; Therapeutic; Tryptophan; Vaccinia; Work; body system; cell type; craniofacial; cytokine; defined contribution; experience; improved; in vivo; inflammatory marker; inhibitor; interferon therapy; mouse model; neuroAIDS; neuroinflammation; neurotoxic; neutralizing antibody; novel; overexpression; pathogen; pre-clinical; receptor; response; therapy development; tool; trait

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).

项目摘要。 21 三体 (T21) 是人类中最常见的染色体异常，导致 会导致唐氏综合症 (DS) 的病症。 DS 患者经历着独特的疾病谱 相对于典型人群，他们可以免受某些疾病的侵害，例如实体癌症和 易患其他疾病，包括阿尔茨海默病、造血系统恶性肿瘤和许多自身免疫性疾病 失调。尽管经过数十年的研究，DS 病理生理学的分子基础仍不清楚。我们 最近报道，T21 导致干扰素 (IFN) 反应的组成型激活，可能是由于 chr21 上存在 6 个 IFN 受体中的 4 个。该项目的中心假设是过度活跃 IFN 信号传导有助于 DS 的病理生理学。该提案概述了因果关系 确定 IFN 过度活跃与 DS 相关性之间关系的性质所必需的研究 使用具有三倍 IFN 受体的 DS 小鼠模型来观察表型。 目标 1. 表征免疫刺激对 DS 表型的影响。使用 DS 鼠标模型 通过 IFN 受体的三倍体（称为 Dp16），我们将描述对免疫刺激的反应 TLR 激动剂、聚 (I:C)、IFNα 或 IFNγ 对 1) 这些动物的发育、生长和整体健康，2) 炎症标志物的表达和多种免疫细胞类型的相对丰度，3) 神经炎症和神经变性，4) 学习、记忆和行为。 目标 2. 确定 IFNR 基因剂量对 DS 表型的影响。四号染色体21- 编码的 IFN 受体位于小鼠 16 号染色体的连续簇中。测试 IFN 的影响 受体拷贝数对免疫敏感性的影响，我们将 Dp16 小鼠与我们创建的新品系杂交，其中 所有四种 IFN 受体均已被删除，称为 IFNR4KO，以产生具有两种（“标准化”Dp16）或 IFNR 簇的三个（“三体”Dp16）拷贝。我们还生成了具有片段重复的菌株 IFNR 簇，称为 IFNR3X，我们将用它来测试该区域的三倍是否足以驱动 DS 表型。 目标 3. 测试抗 IFN 疗法对免疫超敏反应和 DS 表型的影响。我们将 临床前评估三种独立抗干扰素策略的治疗潜力：1) 一种新型 JAK1 特异性 目前正在开发用于治疗自身免疫性疾病的抑制剂，2) 干扰素中和痘苗病毒 正在开发用于治疗 HIV 相关神经系统疾病 (HAND) 的蛋白质，以及 3) 触发的“IFN-kinoid” 目前正在开发用于治疗系统性狼疮的 IFNα 中和抗体的生产 红斑狼疮（SLE）。