Genetic characterization of the murine type I Interferon locus

小鼠 I 型干扰素基因座的遗传特征

• 批准号: 8623890
• 负责人: CHRISTIAN W SCHINDLER
• 金额: $ 23.7万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-12-10 至 2015-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8623890
• 关键词: Adoptive Transfer; Antiviral Agents; Attention; Autoimmune Diseases; Autoimmunity; Biological Process; CD8-Positive T-Lymphocytes; CD8B1 gene; Chromosomes, Human, Pair 4; Data; Development; Elements; Epithelium; Evaluation; Family; Family member; Genes; Genetic; Hematopoietic stem cells; Homeostasis; Human; IFNAR1 gene; Immune; Immune response; Immunologic Monitoring; Individual; Interferon Activation; Interferon Type I; Interferon Type II; Interferons; Knockout Mice; Malignant Neoplasms; Mediating; Microbe; Mus; Natural Killer Cells; Pattern; Play; Psoriasis; RNA Sequence Analysis; Regulation; Reporting; Role; Signal Transduction; Syndrome; Systemic Lupus Erythematosus; T-Lymphocyte; Therapeutic; Tissues; Viral; adaptive immunity; atopy; autocrine; base; cytokine; design; embryonic stem cell; genetic pedigree; in vivo; insight; interest; member; microbiome; pathogen; pressure; public health relevance; receptor; response; tool; tumor; type I interferon receptor; vector

In addition to their potent antiviral activity, type I Interferons (IFN-Is) are increasingly recognized for the important role they play in regulating immune homeostasis, both basally and during an immune challenge. Intriguingly, recent studies suggest the microbiome may play an important role in directing basal activity, which notably includes regulation of hematopoietic stem cells (HSCs), and several lineages they give rise to (e.g., DCs, NK cells & CD8 T-cells). IFN-Is also play an important role during the innate response to viral and bacterial pathogens, whereupon they direct the transition to an effective adaptive response. Consistent with this, IFN-Is have recently been found to play a prominent role in several autoimmune diseases (e.g., systemic lupus erythematosis [SLE], Sj¿gren's syndrome, psoriasis & atopy) and in tumor immunosurveillance. Reflecting these important discoveries have been renewed interest in developing more specific IFN-I based therapeutics to treat autoimmunity, cancer and to manipulate HSCs. Remarkably, in humans the IFN-I family consists of 17 well-curated members, at least half of which are highly conserved, raising the intriguing question of whether they serve distinct biological functions. Unfortunately, the size of the IFN-I locus has precluded the development of effective tools to explore this important question. To this end we have developed targeting vectors that will enable us to either delete the entire IFN-I locus (i.e., IFN-Ilocus-/- mice) or to generate mice in which only the IFN-¿ gene is retained (i.e., IFN-¿only mice). The latter mouse will help evaluate the prevailing notion that IFN-¿ directs the basal IFN-I response. Two aims are proposed to complete the development and analysis of these mice. These data will be vital for subsequent studies in which these two lines will be exploited to explore the role that individual IFN-Is play in vivo. Aim I. Exploit IFN-Ilocus-/- and IFN-¿only mice to explore the role IFN-¿ plays in regulating basal immune homeostasis. This will include evaluation of HSC and NK cell compartments. Aim II. Exploit IFN-Ilocus-/- and IFN-¿ mice to explore the role IFN-¿ plays in directing both only robust innate and adaptive responses to specific microbes.

除了它们强大的抗病毒活性外，I型干扰素(干扰素-IS)越来越多地 认识到它们在调节免疫动态平衡方面发挥着重要作用，在基础和 在一场免疫挑战中。有趣的是，最近的研究表明，微生物群可能在 在指导基础活动方面发挥重要作用，其中尤其包括对造血干细胞的调节 细胞(HSCs)，以及它们产生的几个谱系(例如DC、NK细胞和CD8T细胞)。干扰素-IS 在对病毒和细菌病原体的先天反应中也起着重要作用， 于是，它们引导着向有效的适应性反应的过渡。与此一致的是， 最近发现干扰素-1在几种自身免疫性疾病中起着重要作用(例如， 系统性红斑狼疮[SLE]、干燥综合征、银屑病和特应性皮肤病)和肿瘤 免疫监控。反映这些重要发现的是重新引起人们对 开发更特异的基于干扰素-I的治疗药物来治疗自身免疫、癌症和 操纵造血干细胞。 值得注意的是，在人类中，干扰素-I家族由17个精心策划的成员组成，至少有一半 它们是高度保守的，这引发了一个有趣的问题：它们是否提供不同的服务 生物功能。不幸的是，干扰素-I基因座的大小已经排除了发生 探索这一重要问题的有效工具。为此，我们开发了目标定位 载体将使我们能够删除整个干扰素-I基因座(即，干扰素-ILocus-/-小鼠)或 产生只保留干扰素基因的小鼠(即，仅保留干扰素基因的小鼠)。后一种鼠标 将有助于评估主流概念，即干扰素-β指导基本的干扰素-I反应。 为了完成这些小鼠的开发和分析，提出了两个目标。这些 数据将对后续研究至关重要，在这些研究中，这两条线将被利用来探索 个体干扰素在体内发挥的作用。 目的I.利用干扰素-Ilocus-//-和单纯干扰素-β小鼠，探索干扰素-β在调节中的作用 基础免疫平衡。这将包括对HSC和NK细胞分室的评估。 目的II.利用干扰素-ILocus-/-和干扰素-β小鼠，探索干扰素-β在指导两者中的作用 仅限 对特定微生物的强大的先天和适应性反应。