A new mouse model of severe asthma

一种新的严重哮喘小鼠模型

基本信息

批准号：
10259944
负责人：
Samir Kelada
金额：
$ 23.33万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-05-19 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10259944
关键词：
Address Adrenal Cortex Hormones Affect Age Agonist Allergens Allergic inflammation Antibody Therapy Asthma BALB/cJ Mouse Backcrossings Biological Products Biological Response Modifier Therapy Candidate Disease Gene Cells Cessation of life Chronic Clinical Communities Data Dendritic Cells Dose Eosinophilia Epithelial Epithelial Cells Event Exhalation Exposure to Fatal Outcome Future Gene Expression Genetic Genetic Crosses Goals Grant Health Care Costs Histologic House Dust Mite Allergens Hypersensitivity IgE Immune Immune response Immunologics Immunology Inflammation Inhalation Innate Immune Response Interleukin-1 alpha Interleukin-13 Interleukin-4 Interleukin-5 Intranasal Administration Investigation Leukotrienes Licensing Lung Lymphoid Cell Maps Measures Modeling Mucous body substance Mus Natural Immunity Nitric Oxide Outcome Pathway interactions Patients Phenotype Population Prevalence Production Publishing Pyroglyphidae Quality of life Quantitative Trait Loci Research Resistance Role Serum Severities Societies Sputum Steroid Resistance Steroids Stimulus Susceptibility Gene Symptoms T-Lymphocyte TSLP gene Testing adaptive immune response adaptive immunity airway epithelium airway hyperresponsiveness airway inflammation airway obstruction airway remodeling allergic airway disease allergic airway inflammation asthmatic patient cell type cytokine eosinophilic inflammation experimental study genetic variant genomic locus improved mouse genetics mouse model muscle hypertrophy new therapeutic target novel therapeutic intervention novel therapeutics periostin respiratory respiratory smooth muscle sex targeted agent urgent care whole genome

项目摘要

Project Summary Severe asthma comprises ~10% of all asthma cases but accounts for a disproportionately high degree of asthma health care costs and causes substantial decrements in quality of life for patients. Clinically, this form of asthma is defined by inadequate symptom control despite treatment with high-dose inhaled corticosteroids combined with a long-acting β2-agonist (LABA) or leukotriene modifier. Persistent airway obstruction, increased urgent care utilization, and near-fatal events are also features of severe asthma. The “Type 2-high” (T2-high) form of severe asthma is a common severe asthma sub-type that is characterized by sputum eosinophilia, elevated fraction of exhaled nitric oxide, and increased serum periostin. While new, antibody- based treatment approaches for T2-high asthma have come online, these treatment approaches are only partially effective and do not sufficiently alleviate asthma symptoms and quality of life metrics. Thus, there is still an unmet need for new therapeutics for severe Type 2-high asthma. To address this need, we sought to create/identify a new model of severe T2-high asthma that could be used to identify and test new therapeutic approaches. We identified a strain from the Collaborative Cross mouse genetics reference population, namely CC011/UncJ (hereafter referred to as CC011), that develops extremely high levels of airway eosinophilia, total and HDM-specific IgE, and airway hyper-responsiveness after repeated house dust mite (HDM) allergen exposure (25 µg/treatment by intranasal administration, 3x/week for 5 weeks). Most impressively, CC011 mice consistently died after HDM exposure during weeks 3-4 of treatment, whereas there were no deaths among PBS treated CC011 mice or any other 30 CC strains tested. Importantly, steroid treatment did not ameliorate eosinophilic airway inflammation in this strain. Thus, CC011 represents a new model of severe, T2-high asthma. To further the utility of this of this model, the genetic and immunologic basis of this phenotype need to be determined. In the first aim, we will identify which cell types and pathways are integrally involved in CC011’s innate and adaptive immune responses to HDM. We will determine if allergic inflammation is T cell-dependent and if CD4+ Th2 cell priming is augmented in CC011 mice compared to BALB/cJ mice. We will investigate if airway epithelial cell-derived alarmins (IL-25, IL-33, TSLP, IL-1α/β) are increased in CC011 mice and whether neutralization of these cytokines ameliorates allergic inflammation. Finally, we will determine if allergen- induced expansion and activation of ILC2s are enhanced in CC011 mice. In the second aim, we will identify the genetic loci that harbor CC011’s susceptibility alleles using a quantitative trait locus mapping approach, and then leverage whole genome sequence data and gene expression data from CC011 and other strains to identify candidate genes. These candidate genes will become the focus of future investigations. In total, our results will establish CC011+HDM as a new model of T2-high severe asthma, enabling its widespread use to identify and test new therapeutic approaches.

项目概要严重哮喘约占所有哮喘病例的 10%，但所占比例极高。临床上，这种形式的哮喘会增加医疗费用并导致患者生活质量大幅下降。哮喘的定义是尽管使用大剂量吸入皮质类固醇治疗但症状控制不充分与长效 β2 激动剂 (LABA) 或白三烯调节剂联合使用，紧急护理利用率的增加和近乎致命的事件也是严重哮喘的特征。（T2-高）形式的严重哮喘是一种常见的严重哮喘亚型，其特征是痰嗜酸性粒细胞增多、呼出一氧化氮分数升高以及血清骨膜素增加。基于 T2 高哮喘的治疗方法已经上线，这些治疗方法仅因此，部分有效并且不能充分缓解哮喘症状和生活质量指标。严重 2 型高度哮喘的新疗法的需求仍未得到满足。为了满足这一需求，我们试图解决这一问题。创建/识别严重 T2 高哮喘的新模型，可用于识别和测试新的治疗方法我们从协作交叉小鼠遗传学参考群体中鉴定出一个品系，即 CC011/UncJ（以下简称 CC011），出现极高水平的气道嗜酸性粒细胞总数和 HDM 特异性 IgE，以及反复接触屋尘螨 (HDM) 过敏原后的气道高反应性暴露（25 µg/鼻内给药治疗，每周 3 次，持续 5 周）。在治疗第 3-4 周期间，暴露于 HDM 后始终死亡，而 PBS 治疗 CC011 小鼠或任何其他 30 个测试的 CC 品系，重要的是，类固醇治疗并没有改善。因此，CC011 代表了严重 T2 高的新模型。为了进一步利用该模型，需要了解该表型的遗传和免疫学基础。在第一个目标中，我们将确定哪些细胞类型和途径与 CC011 密切相关。我们将确定对 HDM 的先天性和适应性免疫反应是否依赖于 T 细胞。与 BALB/cJ 小鼠相比，CC011 小鼠的 CD4+ Th2 细胞启动是否增强。 CC011 小鼠中气道上皮细胞衍生的警报素（IL-25、IL-33、TSLP、IL-1α/β）增加，并且是否这些细胞因子的中和可以改善过敏性炎症。 CC011 小鼠中 ILC2 的诱导扩增和激活得到增强。在第二个目标中，我们将确定使用数量性状位点作图方法确定含有 CC011 易感性等位基因的遗传位点，以及然后利用 CC011 和其他菌株的全基因组序列数据和基因表达数据确定候选基因。这些候选基因将成为我们未来研究的重点。结果将确立 CC011+HDM 作为 T2 高严重哮喘的新模型，使其能够广泛用于确定并测试新的治疗方法。