Allergic inflammation in genetic models of lung ILC2 deficiency

肺 ILC2 缺陷遗传模型中的过敏性炎症

基本信息

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
项目类别：
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

项目摘要

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 2 型淋巴细胞（ILC2，也称为天然辅助细胞或核细胞）与广泛传播的传染病和过敏性疾病密切相关。通过驻留在粘膜屏障并响应上皮源性细胞因子（例如 IL-33 和 IL-25），它们快速释放早期 2 型细胞因子，促进适应性 CD4 T 细胞的 Th2 炎症反应和 B 细胞的 IgE 产生。然而，在缺乏分子特征的情况下，ILC2 谱系的定义仍然是暂定的，并且有些争议。此外，虽然它们与其他适应性和先天性淋巴细胞一样源自相同的共同淋巴前体细胞（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。该项目建立在对我们实验室生产的 PLZF-IRES-GFPCre 报告小鼠的初步研究的基础上，该研究表明转录因子 PLZF（之前被确定为产生类先天性 IL-4/IL-13 的 NKT 细胞谱系的特征）也是在 ILC2 的发育过程中高水平表达。中心假设是 PLZF 在 ILC2 的发育中发挥关键功能，并且 PLZF 报告/删除小鼠可用于遗传跟踪和操纵 ILC2 前体及其成熟后代。本应用的目的是使用 PLZF-IRES-GFPCre 小鼠来鉴定 ILC2 的骨髓前体，表征其分子程序，并在与 ROSA26-FL-STOP-FL-Tomato 小鼠杂交后通过命运图谱定义其后代。此外，该项目将测试体内基因操纵或消除 ILC2 的各种方法，作为表征其在生理学和过敏性气道炎症中功能的前奏。具体目标是：1）表征CLP的PLZFhi子集； 2) 确定PLZF在ILC2发育和功能中的作用； 3) 创建ILC2缺陷型小鼠模型用于过敏性气道炎症的研究。该项目具有创新性，因为它探索了PLZF表达在专门从事2型反应的先天和类先天谱系之间共享的新想法，并且因为它将产生用于体内ILC2研究的新模型和试剂。这将标志着我们理解和进一步操纵先天免疫在由 2 型免疫引起或治愈的全球疾病中的作用的能力发生重大转变。拟议的研究意义重大，因为它将大大增强我们对先天淋巴细胞谱系发育的理解。所开发的概念和工具将使开发针对寄生虫和过敏原先天免疫的不同成分的药物成为可能。