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.

除了其有效的抗病毒活性之外，I型干扰素（IFN-1）越来越多地被用于治疗癌症。 公认的重要作用，他们发挥调节免疫稳态，无论是基础和 在免疫挑战中。有趣的是，最近的研究表明，微生物组可能发挥了重要作用。 在指导基础活动中的重要作用，特别是包括造血干细胞的调节 细胞（HSC），以及它们产生的几种谱系（例如，DC、NK细胞和CD 8 T细胞）。干扰素样 在对病毒和细菌病原体的先天反应中也发挥重要作用， 于是它们引导过渡到有效的适应性反应。与此相一致， 最近发现IFN-1在几种自身免疫性疾病（例如， 系统性红斑狼疮[SLE]、干燥综合征、银屑病和特应性）和肿瘤 免疫监视反映这些重要发现的是， 开发更特异性的基于IFN-1的治疗剂以治疗自身免疫、癌症， 操纵HSC。 值得注意的是，在人类中，IFN-I家族由17个精心挑选的成员组成，其中至少有一半是 它们是高度保守的，这就提出了一个有趣的问题， 生物功能。不幸的是，IFN-I基因座的大小阻止了 有效的工具来探索这个重要的问题。为此，我们制定了针对 使我们能够删除整个IFN-1基因座（即，IFN-1基因座-/-小鼠）或 产生仅保留IFN-γ基因的小鼠（即，仅IFN-γ小鼠）。最后一只老鼠 将有助于评估IFN-γ指导基础IFN-Ⅰ应答的流行观念。 提出了两个目标来完成这些小鼠的开发和分析。这些 数据将是至关重要的后续研究中，这两条线将被利用来探索 单个IFN-1在体内发挥的作用。 艾姆岛利用IFN-γ基因座-/-和IFN-γ单用小鼠探讨IFN-γ在调节 基础免疫稳态这将包括HSC和NK细胞区室的评价。 Aim II.利用IFN-Ilocus-/-和IFN-<$小鼠来探索IFN-<$在指导两者中的作用。 只 对特定微生物的强大先天和适应性反应。