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: 10163797
• 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/10163797
• 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; HIV; 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; 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/antagonist; interferon therapy; mouse model; nervous system disorder; 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）是人类群体中最常见的染色体异常， 唐氏综合症（Down Syndrome，DS）患有DS的个体经历独特的疾病谱 相对于典型人群，他们受到保护，免受某些疾病，如实体癌， 易患其他疾病，包括阿尔茨海默氏病，造血系统恶性肿瘤和一系列自身免疫性疾病。 紊乱尽管经过数十年的研究，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（IFN）应答的组成性激活，这可能是由于 chr 21上存在六种IFN受体中的四种。这个项目的中心假设是， IFN信号转导有助于DS的病理生理学。该提案概述了因果关系 确定IFN活性亢进和DS相关性之间关系的性质所需的调查 表型使用具有三重IFN受体的DS小鼠模型。 目标1.表征免疫刺激对DS表型的影响。使用DS小鼠模型 随着IFN受体（称为Dp 16）的三倍，我们将用以下方法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、生长和总体健康的影响，2） 炎性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，以及4）学习、记忆和行为。 目标2.确定IFNR基因剂量对DS表型的贡献。四条21号染色体- 编码的IFN受体位于小鼠16号染色体上的连续簇中。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Dp 16小鼠与我们创建的新品系杂交， 所有四种IFN受体都被删除，称为IFNR 4KO，以产生具有两种（“标准化”Dp 16）或两种（“标准化”Dp 16）的小鼠。 IFNR簇的三个（“三体”Dp 16）拷贝。我们还产生了一个片段重复的菌株 IFNR簇的三倍，称为IFNR 3X，我们将使用它来测试该区域的三倍是否足以驱动DS 表型 目标3.检测抗IFN治疗对免疫超敏反应和DS表型的影响。我们将 临床前评估三种独立的抗干扰素策略的治疗潜力：1）一种新的JAK 1特异性抗干扰素策略， 目前正在开发的用于治疗自身免疫性疾病的抑制剂，2）IFN-中和牛痘 蛋白质正在开发用于HIV相关的神经系统疾病（HAND），和3）一种“IFN-类激酶”， 目前正在开发用于治疗系统性狼疮的IFNα中和抗体的生产 红斑性狼疮（SLE）。