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）：拟议研究的目的是确定调节2型先天淋巴样细胞（ILC2）的新机制。 ILC2是最近发现的谱系阴性淋巴细胞的种群，该淋巴细胞响应上皮细胞因子IL-33和TSLP而产生Th2细胞因子。 ILC2在动物模型中有助于哮喘表型，并存在于人肺中。具体而言，我们假设RNA结合蛋白RBM3通过Th2细胞因子mRNA稳定化控制人和小鼠ILC2 TH2细胞因子的产生和先天2型肺反应。我们将对WT和RBM3基因敲除小鼠的气道管理过敏原，IL-33和TSLP挑战，并评估肺ILC2 TH2 TH2细胞因子的产生和增殖，以及Bal嗜酸性粒细胞，上皮粘液产生，底基型渗透性和空气高压率高。我们还将进行ILC2的继承转移研究，并产生RBM3缺陷IL-13报告基因小鼠，以定义在过敏原，IL-33和TSLP引起的气道炎症期间ILC2中RBM3的作用。我们将对来自WT和RBM3基因敲除小鼠的纯化的ILC2以及用IL-33和TSLP刺激的人类RMB3 siRNA敲低ILC2进行体外研究，并评估ILC2 TH2 TH2细胞因子产生和增殖水平。此外，我们将执行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。我们预计会发现，INB3促进ILC2 TH2细胞因子mRNA稳定性，并控制ILC2 TH2 TH2细胞因子在体外和体内的产生。拟议研究的新颖性包括使用新型试剂（RBM3 - / - ，RBM3 - / - RAG2 - / - 和RBM3 - / - / - / - / - / - /YFP-IL-13记者小鼠）以及揭示新的途径（RNA结合蛋白），从而调节了最近发现的细胞类型（ILC2）（ILC2），从而有助于发炎。重要的是，调节ILC2功能的分子的发现可能揭示了新的治疗靶标，以减少哮喘和过敏性疾病中的ILC2激活。