Allergic inflammation in genetic models of lung ILC2 deficiency

肺 ILC2 缺陷遗传模型中的过敏性炎症

• 批准号: 8576628
• 负责人: ALBERT S. BENDELAC
• 金额: $ 37.07万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8576628
• 关键词: Aggressive behavior; Alleles; Allergens; Allergic; Allergic Disease; Allergic inflammation; Asthma; B-Lymphocytes; Biology; Bone Marrow; CD4 Positive T Lymphocytes; Cell Lineage; Cells; Communicable Diseases; Defect; Development; Disease; Engineering; Epithelial; Genetic Models; Goals; Health; Helminths; Helper-Inducer T-Lymphocyte; Human; IL4 gene; IL7R gene; IgE; Immune; Immunity; Inflammatory Response; Interleukin-13; Interleukin-4; Internal Ribosome Entry Site; Knock-in Mouse; Knowledge; Laboratories; Lung; Lung diseases; Lymphocyte; Lymphoid; Lymphoid Cell; Maps; Mission; Modeling; Molecular; Molecular Profiling; Mus; Natural Immunity; Parasites; Parasitic Diseases; Physiology; Population; Production; Property; Public Health; Reagent; Reporter; Research; Role; Signal Transduction; Testing; Tomatoes; United States National Institutes of Health; Work; ZNF145 gene; allergic airway inflammation; allergic response; cytokine; human disease; in vivo; innovation; lung development; model development; mouse model; novel; novel strategies; prevent; programs; public health relevance; response; tool; transcription factor

DESCRIPTION (provided by applicant): Innate type 2 lymphocytes (ILC2, also called natural helper cells or nuocytes) are critically involved in widespread infectious and allergic diseases. By residing at mucosal barriers and responding to epithelial-derived cytokines such as IL-33 and IL-25, they rapidly release the early type 2 cytokines that promote the Th2 inflammatory responses of adaptive CD4 T cells and the IgE production of B cells. However, the definition of the ILC2 lineage remains tentative and somewhat controversial in the absence of molecular signature. Furthermore, while they derive from the same common lymphoid precursors (CLP) as other adaptive and innate lymphocytes, their developmental intermediates and their relationship with other related lineages are unknown. This project builds on preliminary studies of PLZF-IRES-GFPCre reporter mice produced in our laboratory showing that the transcription factor PLZF, previously identified as the signature of the innate-like IL- 4/IL-13-producing NKT cell lineage, is also expressed at high levels during the development of ILC2s. The central hypothesis is that PLZF exerts critical functions in the development of ILC2s and that PLZF- reporter/deleter mice can be used to genetically track and manipulate ILC2 precursors and their mature progeny. The objective of this application is to use PLZF-IRES-GFPCre mice to identify the bone marrow precursors of ILC2, characterize their molecular program and define their progeny through fate mapping after crossing to ROSA26-FL-STOP-FL-Tomato mice. Furthermore, the project will test various approaches to genetically manipulate or ablate ILC2 in vivo as a prelude to characterizing their function in physiology and in allergic airway inflammation. The specific aims are: 1) to characterize the PLZFhi subset of CLP; 2) to determine the role of PLZF in ILC2 development and function; 3) to create ILC2-defective mouse models for studies of allergic airway inflammation. The project is innovative because it explores the novel idea that PLZF expression is shared across innate and innate-like lineages specializing in type 2 responses and because it will produce new models and reagents for studies of ILC2s in vivo. This would signal a major shift in our ability to understand and further manipulate the role of innate immunity in worldwide diseases caused or cured by type 2 immunity. The proposed research is significant because it will considerably enhance our understanding of innate lymphocyte lineage development. The concepts and tools developed will make it possible to develop agents that target distinct components of innate immunity to parasites and allergens.

描述（由申请人提供）：先天类型2型淋巴细胞（ILC2，也称为天然辅助细胞或刺激细胞）与广泛的传染性和过敏性疾病有关。通过居住在粘膜屏障并响应上皮衍生的细胞因子，例如IL-33和IL-25，它们迅速释放了促进自适应CD4 T细胞和B细胞IgE产生的Th2炎症反应的早期2型细胞因子。然而，在没有分子特征的情况下，ILC2谱系的定义仍然是暂时的，并且有些争议。此外，尽管它们来自与其他适应性和先天淋巴细胞相同的常见淋巴前体（CLP），但它们的发育中间体及其与其他相关谱系的关系尚不清楚。该项目基于我们实验室中产生的PLZF-IRES-GFPCRE报告基因小鼠的初步研究表明，在ILC2S的开发过程中，在高水平的高水平上也表达了先前确定为先前被确定为先天性IL-4/IL-13产生的NKT细胞谱系的签名的转录因子PLZF。中心假设是，PLZF在ILC2S的发展中发挥关键功能，并且PLZF-Reporter/Deleter小鼠可用于跟踪和操纵ILC2前体及其成熟后代。该应用的目的是使用PLZF-IRES-GFPCRE小鼠鉴定ILC2的骨髓前体，表征其分子程序，并在越过Rosa26-Fl-Stop-Fl-Fl-Tomato小鼠后通过命运图来定义其后代。此外，该项目将测试各种在体内操纵或释放ILC2的方法，以表征其在生理学和过敏性气道炎症中的功能。具体目的是：1）表征CLP的PLZFHI子集； 2）确定PLZF在ILC2开发和功能中的作用； 3）创建ILC2缺陷的小鼠模型来研究过敏性气道炎症。该项目具有创新性，因为它探讨了一个新颖的想法，即PLZF表达在专门从事2型响应的先天和先天般的谱系中共享，并且它将生成新的模型和试剂，以研究体内ILC2S的研究。这将表明我们理解和进一步操纵先天免疫在全球疾病中的作用或通过2型免疫治愈的世界疾病的作用发生了重大转变。拟议的研究很重要，因为它将大大增强我们对先天淋巴细胞谱系发展的理解。开发的概念和工具将使开发针对寄生虫和过敏原的不同组成部分的代理。