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外，I 型干扰素 (IFN-Is) 越来越多地被 公认它们在调节基础和免疫稳态方面发挥的重要作用 在免疫挑战期间。有趣的是，最近的研究表明微生物组可能发挥着重要作用 在指导基础活动中发挥重要作用，特别是造血干的调节 细胞 (HSC) 及其产生的几种谱系（例如 DC、NK 细胞和 CD8 T 细胞）。干扰素Is 在对病毒和细菌病原体的先天反应中也发挥着重要作用， 随后，他们指导过渡到有效的适应性反应。与此相一致的是， 最近发现 IFN-Is 在多种自身免疫性疾病（例如， 系统性红斑狼疮 [SLE]、干燥综合征、牛皮癣和特应性）和肿瘤 免疫监视。反映这些重要发现的人们重新燃起了对 开发更具体的基于 IFN-I 的疗法来治疗自身免疫、癌症和 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，其中至少一半是 它们是高度保守的，提出了一个有趣的问题：它们是否具有独特的作用 生物学功能。不幸的是，IFN-I基因座的大小阻碍了 探索这个重要问题的有效工具。为此，我们制定了目标 载体将使我们能够删除整个 IFN-I 基因座（即 IFN-Ilocus-/- 小鼠）或 产生仅保留 IFN-¿ 基因的小鼠（即，仅 IFN-¿ 小鼠）。后者的鼠标 将有助于评估 IFN-¿ 指导基础 IFN-I 反应的普遍观点。 提出了两个目标来完成这些小鼠的开发和分析。这些 数据对于后续研究至关重要，其中将利用这两条线来探索 单个 IFN-Is 在体内发挥的作用。 目标 I. 利用 IFN-Ilocus-/- 和 IFN-only 小鼠来探索 IFN-¿ 在调节中的作用 基础免疫稳态。这将包括 HSC 和 NK 细胞区室的评估。 目标二。利用 IFN-Ilocus-/- 和 IFN-¿ 小鼠探索 IFN-¿ 在指导两者中的作用 仅有的 对特定微生物的强大的先天和适应性反应。