Genetic characterization of the murine type I Interferon locus

小鼠 I 型干扰素基因座的遗传特征

基本信息

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
项目类别：
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

项目摘要

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.

除了潜在的抗病毒活性外，I型干扰素（IFN-IS）越来越多认可他们在调节免疫稳态的重要作用，无论在免疫挑战中。有趣的是，最近的研究表明，微生物组可能发挥指导基本活动的重要作用，这特别包括调节造血茎细胞（HSC）及其产生的几条线（例如DC，NK细胞和CD8 T细胞）。 ifn-is 在对病毒和细菌病原体的先天反应中也起着重要作用，因此，他们将过渡引导到有效的自适应反应。与此一致最近发现IFN-I在多种自身免疫性疾病中起着重要作用（例如，全身性红斑狼疮[SLE]，sj¿格伦综合征，牛皮癣和特应症）和肿瘤中免疫监视。反映这些重要发现已引起人们对开发更具体的基于IFN-I的理论来治疗自身免疫性，癌症和to 操纵HSC。值得注意的是，在人类中，IFN-i家族由17个策划成员组成这是高度保守的，提出了一个有趣的问题，即它们是否服务于独特生物功能。不幸的是，IFN-I基因座的大小排除了探索这个重要问题的有效工具。为此，我们开发了目标使我们能够删除整个IFN-i locus（即ifn-ilocus - / - 鼠标）的向量或产生仅保留IFN-€基因的小鼠（即仅IFN小鼠）。后一种鼠标将有助于评估IFN-指导基本IFN-I响应的普遍观念。提出了两个目标来完成对这些小鼠的发展和分析。这些数据对于随后的研究至关重要，其中将探索这两条线以探索个体IFN-IS在体内发挥的作用。 AIM I.利用IFN-ilocus - / - 和IFN-¿ 基本的免疫稳态。这将包括评估HSC和NK细胞室。目标II。利用IFN-ilocus - / - 和Ifn-€鼠标探索IFN-€的角色指导两者仅有的对特定微生物的天生和自适应反应。