Genetic characterization of the murine type I Interferon locus

描述(申请人提供)：除了其强大的抗病毒活性，I型干扰素(干扰素-IS)因其在基础和免疫挑战期间调节免疫动态平衡的重要作用而日益受到认可。有趣的是，最近的研究表明，微生物组可能在指导基础活动方面发挥重要作用，尤其是调节造血干细胞(HSCs)及其产生的几个谱系(例如DC、NK细胞和CD8T细胞)。在对病毒和细菌病原体的先天反应中，干扰素-1也发挥着重要的作用，从而指导向有效的适应性反应的转变。与此一致的是，最近发现干扰素-IS在几种自身免疫性疾病(如系统性红斑狼疮、干燥综合征、牛皮癣和特应性皮肤病)和肿瘤免疫监测中发挥着重要作用。反映这些重要发现的是，人们对开发更具体的基于干扰素-I的治疗药物重新产生了兴趣，以治疗自身免疫、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个精心挑选的成员组成，其中至少有一半高度保守，这引发了一个有趣的问题：它们是否具有不同的生物学功能。不幸的是，其大小 干扰素-I基因座阻碍了开发有效的工具来探索这一重要问题。为此，我们开发了靶向载体，使我们能够删除整个干扰素-I基因座(即，干扰素-ILocus-/-小鼠)或产生仅保留干扰素基因的小鼠(即，仅保留干扰素基因的小鼠)。后一种小鼠将帮助评估主流观点，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。这些数据对于后续的研究将是至关重要的，在这些研究中，这两个品系将被利用来探索单个干扰素-1在体内所起的作用。目的1.利用IF-ILOCUS-/-和单纯干扰素-β小鼠，探讨干扰素-β在调节基础免疫动态平衡中的作用。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在引导对特定微生物的强健的先天反应和适应性反应中所起的作用。

DESCRIPTION (provided by applicant): 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 IF-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.