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RBM3 regulation of type 2 innate lymphoid cells in allergic inflammation

RBM3 对过敏性炎症中 2 型先天淋巴细胞的调节

基本信息

批准号：
8799448
负责人：
TAYLOR A DOHERTY
金额：
$ 47.54万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-11-10 至 2019-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8799448
关键词：
Adoptive Transfer Allergens Allergic Allergic Disease Allergic inflammation Amino Acid Motifs Animal Model Asthma B-Lymphocytes Biological Assay Biology Blood Cells Data Elements Epithelial Exclusion Extrinsic asthma Future Genetic Goals Human Immune In Vitro Infiltration Interleukin-13 Interleukin-5 Knockout Mice Leukocytes Lung Lung Inflammation Lymphocyte Lymphoid Cell Mediating Messenger RNA Modeling Molecular Monitor Mucous body substance Mus Nasal Polyps Northern Blotting Pathogenesis Pathway interactions Phenotype Population Production RNA Binding RNA-Binding Proteins Reagent Regulation Reporter Research Role Small Interfering RNA T-Lymphocyte TSLP gene Testing Time Transcript airway hyperresponsiveness airway inflammation antigen challenge base cell type cytokine eosinophil in vivo knock-down mRNA Stability new therapeutic target novel public health relevance response therapeutic target

项目摘要

DESCRIPTION (provided by applicant): The goal of the proposed research is to identify novel mechanisms that regulate type 2 innate lymphoid cells (ILC2). ILC2 are a recently discovered population of lineage-negative lymphocytes that produce Th2 cytokines in response to epithelial cytokines IL-33 and TSLP. ILC2 contribute to an asthma phenotype in animal models and are present in human lungs. Specifically, we hypothesize that the RNA-binding protein RBM3 controls human and mouse ILC2 Th2 cytokine production and innate type 2 lung responses through Th2 cytokine mRNA stabilization. We will administer allergen, IL-33, and TSLP challenges to the airways of WT and RBM3 knockout mice and assess lung ILC2 Th2 cytokine production and proliferation, as well as levels of BAL eosinophils, epithelial mucus production, peribronchial infiltration and airway hyperresponsiveness. We will also perform ILC2 adoptive transfer studies and generate RBM3 deficient IL-13 reporter mice to define the role of RBM3 in ILC2 during allergen, IL-33, and TSLP-induced airway inflammation. We will perform in vitro studies with purified ILC2 from WT and RBM3 knockout mice as well as human RMB3 siRNA knockdown ILC2 stimulated with IL-33 and TSLP and assess levels of ILC2 Th2 cytokine production and proliferation. Further, we will perform mRNA stability assays to determine whether RBM3 controls ILC2 function by stabilizing Th2 cytokine mRNAs. We expect to find that RMB3 promotes ILC2 Th2 cytokine mRNA stability and controls ILC2 Th2 cytokine production in vitro and in vivo. The novelty of the proposed studies includes use of novel reagents (RBM3-/-, RBM3-/-RAG2-/-, and RBM3-/-/YFP-IL-13 reporter mice) and uncovering a novel pathway (RNA binding protein) regulating a recently discovered cell type (ILC2) that contributes to allergic inflammation. Importantly, the discovery of molecules that regulate ILC2 function may reveal novel therapeutic targets to reduce ILC2 activation in asthma and allergic disease.

描述（由申请人提供）：拟议研究的目标是确定调节 2 型先天淋巴细胞 (ILC2) 的新机制。 ILC2 是最近发现的谱系阴性淋巴细胞群，可响应上皮细胞因子 IL-33 和 TSLP 产生 Th2 细胞因子。 ILC2 会导致动物模型中的哮喘表型，并且存在于人类肺部中。具体来说，我们假设 RNA 结合蛋白 RBM3 通过 Th2 细胞因子 mRNA 稳定来控制人和小鼠 ILC2 Th2 细胞因子的产生和先天 2 型肺反应。我们将对 WT 和 RBM3 敲除小鼠的气道进行过敏原、IL-33 和 TSLP 攻击，并评估肺 ILC2 Th2 细胞因子的产生和增殖，以及 BAL 嗜酸性粒细胞的水平、上皮粘液产生、支气管周围浸润和气道高反应性。我们还将进行 ILC2 过继转移研究，并生成 RBM3 缺陷的 IL-13 报告小鼠，以确定 RBM3 在过敏原、IL-33 和 TSLP 诱导的气道炎症期间在 ILC2 中的作用。我们将使用来自WT和RBM3敲除小鼠的纯化ILC2以及用IL-33和TSLP刺激的人RMB3 siRNA敲除ILC2进行体外研究，并评估ILC2 Th2细胞因子产生和增殖的水平。此外，我们将进行 mRNA 稳定性测定，以确定 RBM3 是否通过稳定 Th2 细胞因子 mRNA 来控制 ILC2 功能。我们期望发现RMB3在体外和体内促进ILC2 Th2细胞因子mRNA的稳定性并控制ILC2 Th2细胞因子的产生。拟议研究的新颖性包括使用新型试剂（RBM3-/-、RBM3-/-RAG2-/-和RBM3-/-/YFP-IL-13报告小鼠）和揭示调节最近发现的导致过敏性炎症的细胞类型（ILC2）的新途径（RNA结合蛋白）。重要的是，调节 ILC2 功能的分子的发现可能会揭示减少哮喘和过敏性疾病中 ILC2 激活的新治疗靶点。