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：
10407643
负责人：
Samir Kelada
金额：
$ 19.44万
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/10407643
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 Persons 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 immune response 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.

项目摘要严重哮喘占所有哮喘病例的约10％，但占高度高度的哮喘医疗保健成本，并导致患者的生活质量大大降低。在临床上，这种形式哮喘的定义是用高剂量遗传性皮质类固醇来控制症状控制目的地治疗与长效的β2-振动剂（LABA）或白三烯修饰剂结合使用。持续的气道阻塞，紧急护理利用的增加，近乎致命的事件也是严重哮喘的特征。 “ 2型高” （T2高）严重哮喘的形式是一种常见的严重哮喘亚型，其特征是痰嗜酸性粒细胞增长，一氧化氮的耗尽部分升高，血清周期增加。虽然是新的，抗体 - T2高哮喘的基于基于的治疗方法已经在线，这些治疗方法只是部分有效，不能充分缓解哮喘症状和生活质量指标。那是对于严重2型哮喘的新疗法仍然未满足。为了满足这一需求，我们试图创建/识别一种新的严重T2高哮喘的模型，该模型可用于识别和测试新疗法方法。我们从协作跨小鼠遗传学参考人群中确定了一种压力，即 CC011/UNCJ（以下称为CC011），它会发展出极高的气道嗜酸性粒细胞增多和HDM特异性IGE，以及反复的房屋粉尘（HDM）过敏原后气道高反应性暴露（通过鼻内给药25 µg/治疗3倍/周5周）。最令人印象深刻的是CC011小鼠在治疗第3-4周内，HDM暴露后，始终死亡，而之间没有死亡 PBS处理的CC011小鼠或其他30辆CC菌株测试。重要的是，类固醇治疗没有改善在这种菌株中注射嗜酸性气道。这是CC011代表一种新的严重T2高的新模型哮喘。为了进一步促进该模型的实用性，该表型的遗传和免疫学基础需要可以确定。在第一个目标中，我们将确定哪些单元格类型和途径在CC011的对HDM的先天和适应性免疫反应。我们将确定过敏性炎症是否依赖于T细胞如果与BALB/CJ小鼠相比，CC011小鼠中CD4+ TH2细胞启动的增加。我们将调查是否气道上皮细胞衍生的警报（IL-25，IL-33，TSLP，IL-1α/β）在CC011小鼠中增加这些细胞因子的中和可改善过敏性炎症。最后，我们将确定过敏原是否在CC011小鼠中，ILC2S的诱导膨胀和激活增强了。在第二个目标中，我们将确定使用定量性状基因座映射方法携带CC011易感性等位基因的遗传基因座，并且然后利用CC011和其他菌株的整个基因组序列数据和基因表达数据识别候选基因。这些候选基因将成为未来研究的重点。总共，我们的结果将建立CC011+HDM作为T2-高严重哮喘的新模型，从而使其宽度用于使用识别并测试新的治疗方法。