A new mouse model of severe asthma

一种新的严重哮喘小鼠模型

• 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
• 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

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 重症哮喘约占所有哮喘病例的10%，但占比高得不成比例 哮喘的医疗保健成本很高，并导致患者的生活质量大幅下降。临床上，这种形式 哮喘的定义是尽管使用大剂量吸入皮质类固醇治疗，但症状控制不足。 与长效β2-激动剂(LABA)或白三烯调节剂联合使用。持续的呼吸道阻塞， 更多的紧急护理利用率和近乎致命的事件也是严重哮喘的特征。“类型2-高” (T2-高)型重症哮喘是一种常见的以痰为特征的重症哮喘亚型 嗜酸性粒细胞增多，呼出的一氧化氮比例升高，血清骨钙素升高。虽然是新的，但抗体- 基于T2-High哮喘的治疗方法已经上线，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。因此，有 对于严重的2型高度哮喘，对新疗法的需求仍然没有得到满足。为了满足这一需求，我们试图 创建/确定可用于识别和测试新的治疗方法的严重T2高哮喘的新模型 接近了。我们从协作杂交小鼠遗传学参考种群中鉴定出一种菌株，即 CC011/UncJ(下称CC011)，发展为极高水平的呼吸道嗜酸性粒细胞增多症，总共 和HDM特异性IgE，以及反复屋尘(HDM)变应原后的呼吸道高反应性 暴露(25微克/滴鼻给药，每周3次，共5周)。最令人印象深刻的是CC011小鼠 在治疗的3-4周内，接触HDM后持续死亡，而在 PBS处理的CC011小鼠或任何其他30个被测试的CC菌株。重要的是，类固醇治疗并没有改善 该菌株的嗜酸性气道炎。因此，CC011代表了一种新的严重、T2高的模式 哮喘。为了进一步利用这一模型，这种表型的遗传和免疫学基础需要 要下定决心。在第一个目标中，我们将确定哪些细胞类型和途径完整地参与了CC011的S 对HDM的先天和获得性免疫反应。我们将确定过敏性炎症是否依赖T细胞 如果与BALB/CJ小鼠相比，CC011小鼠的CD4+Th2细胞免疫增强。我们将调查是否 IL-25、IL-33、TSLP、IL-1α/β在CC011小鼠呼吸道上皮细胞来源的警示蛋白表达增加 中和这些细胞因子可以缓解过敏性炎症。最后，我们将确定过敏原是否- CC011小鼠体内ILC2s的诱导扩张和激活作用增强。在第二个目标中，我们将确定 用数量性状基因座作图方法定位含有CC011‘S易感等位基因的遗传座位，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未来研究的重点。总的来说，我们的 结果将建立CC011+HDM作为T2-高度重度哮喘的新模型，使其能够广泛应用于 确定和测试新的治疗方法。