Mechanisms of IL-17A-mediated enhancement of asthma severity

IL-17A 介导的哮喘严重程度增强的机制

基本信息

批准号：
8842705
负责人：
Ian Paul Lewkowich
金额：
$ 37.31万
依托单位：
CINCINNATI CHILDRENS HOSP MED CTR
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：
2014-05-01 至 2019-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8842705
关键词：
ATF2 gene Accounting Acute Address Adrenal Cortex Hormones Allergens Animal Model Animals Asthma Automobile Driving Binding CCAAT-Enhancer-Binding Proteins Case-Control Studies Cells Cessation of life Child Childhood Childhood Asthma Chronic Clinical Complex Data Development Disease Dissociation Elements Environmental Exposure Epidemiology Epithelial Cells Exposure to Extrinsic asthma Gene Expression Genes Genetic Transcription Goals Health Hereditary Disease Hospitalization Human Human Cell Line Immune response In Vitro Incidence Indium Individual Interleukin-13 Interleukin-17 Knowledge Lead Link Mediating Minority Groups Molecular Monitor Morbidity - disease rate Mus Mutate NF-kappa B Nose Pathogenesis Pathology Pathway interactions Phosphorylation Play Population Process Production Refractory Resistance Resources Risk STAT6 gene Serum Severities Severity of illness Signal Transduction TNF receptor-associated factor 3 Target Populations Testing Therapeutic Intervention Translating Translational Research Underserved Population activating transcription factor airway hyperresponsiveness asthmatic clinical infrastructure cytokine design experience health disparity in vivo inflammatory lung disease interleukin-13 receptor low socioeconomic status mortality mouse model novel novel therapeutics operation prevent promoter receptor repository response therapeutic target

项目摘要

DESCRIPTION (provided by applicant): Asthma is a chronic, inflammatory disease of the lung that currently afflicts more than 300 million people worldwide. While asthma is mediated by an excessive Th2 immune response to allergens, recent evidence suggests that production of the Th17 cytokine, IL-17A, is associated with the development of more severe disease. While severe asthmatics are at greatest risk for morbidity or death following acute exacerbations, and can be refractory to therapies that are highly effective in individuals with mild disease, the molecular mechanisms whereby IL-17A contributes to the development of severe allergic asthma are ill-defined. A greater understanding of the molecular mechanisms through which IL-17A facilitates severe asthma would provide additional therapeutic targets for populations underserved by current therapies. Using a mouse model we provide evidence that severe asthma is associated with increased IL-17A production, and is compounded by enhanced Il17ra expression and elevated responsiveness to IL-17A. These alterations in IL-17A production and responsiveness exacerbate IL-13-driven STAT6 activation, gene expression, and airway responses. Our preliminary data suggests that IL-17A-mediated enhancement of IL-13-driven responses occur through two, non-mutually independent mechanisms in mouse cells; 1) by causing the dissociation of a complex including IL-13R¿1 and TRAF3, which normally limits IL-13-driven STAT6 phosphorylation, and 2) by activating transcription factors (NF-¿B, C/EBP¿ and C/EBP¿) which can enhance IL-13/STAT6 driven gene expression. While preliminary studies presented here also suggest that similar mechanisms may operate in human cell lines, the extent to which the observations made in our mouse model apply to humans with severe asthma is unclear. Three specific aims are proposed to identify the molecular mechanisms through which IL-17A enhances asthma severity in mice, and humans. Specific Aim 1 will determine if the increased IL-13-driven STAT6 phosphorylation and AHR observed in the presence of IL-17A is the result of the dissociation of the IL- 13R¿1:TRAF3 complex following initiation of IL-17A signaling. Specific Aim 2 will dissect the importance of IL- 17A-driven activation of NF-¿B (canonical versus non-canonical), C/EBP¿ and C/EBP¿ in IL-13/IL-17A synergy in vitro and in vivo. Specific Aim 3 will directly test whether similar synergistic interactions between IL-13 and IL-17A are observed in asthma relevant, primary human cells. Additionally, we will determine whether severe asthma in children is associated, as it is in the mouse, with increased IL-17A production, IL17RA expression, and IL-17A responsiveness. Collectively, the studies proposed in this application will move us beyond the "Th2 paradigm" of allergic asthma, begin to characterize the mechanisms whereby Th17-products trigger the development of severe allergic asthma, and determine whether similar mechanisms may be at play in mice and humans. A better understanding of these mechanisms will enable us to identify novel targets for therapeutic interventions in individuals with severe asthma, a population underserved by current therapies.

描述（由申请人提供）：哮喘是一种慢性炎症性肺部疾病，目前全世界有超过 3 亿人患有哮喘。虽然哮喘是由对过敏原的过度 Th2 免疫反应介导的，但最近的证据表明，Th17 细胞因子的产生， IL-17A 与更严重疾病的发展相关，而严重哮喘患者在急性发作后发病或死亡的风险最大，并且可能难以治疗。虽然 IL-17A 对患有轻度疾病的个体非常有效，但 IL-17A 导致严重过敏性哮喘发展的分子机制尚不明确。更好地了解 IL-17A 促进严重哮喘的分子机制将提供额外的治疗靶点。对于目前治疗不足的人群，我们提供了证据表明严重哮喘与 IL-17A 产生增加有关，并且 IL-17ra 表达增强和对 IL-17A 产生的反应性升高加剧了这些变化。我们的初步数据表明，IL-17A 介导的 IL-13 驱动反应的增强是通过小鼠细胞中两种非相互独立的机制发生的。）通过引起包括 IL-13R 在内的复合物解离¿ 1 和 TRAF3，通常限制 IL-13 驱动的 STAT6 磷酸化，2) 通过激活转录因子（NF-¿B、C/EBP 和 C/EBP ），从而增强 IL-13/STAT6 驱动的基因表达。虽然本文提出的初步研究也表明类似的机制可能在人类细胞系中发挥作用，但我们的小鼠模型中的观察结果适用于患有严重哮喘的人类的程度尚不清楚，因此提出了三个具体目标来确定分子机制。 IL-17A 会增强小鼠和人类的哮喘严重程度具体目标 1 将确定在 IL-17A 存在下观察到的 IL-13 驱动的 STAT6 磷酸化和 AHR 的增加是否是 IL-13R 解离的结果。 1：IL-17A 信号传导启动后的 TRAF3 复合物具体目标 2 将剖析 IL-17A 驱动的 NF-¿ 激活的重要性。 B（规范与非规范），C/EBP¿和 C/EBP¿具体目标 3 将直接测试在哮喘相关的原代人类细胞中是否观察到 IL-13 和 IL-17A 之间的类似协同相互作用。与小鼠一样，儿童哮喘与 IL-17A 产生、IL17RA 表达和 IL-17A 反应性增加相关。总的来说，本申请中提出的研究将使我们超越“Th2”。过敏性哮喘范例”，开始描述 Th17 产物引发严重过敏性哮喘发展的机制，并确定类似的机制是否可能在小鼠和人类中发挥作用。更好地了解这些机制将使我们能够确定新的靶点对患有严重哮喘的个体进行治疗干预，该人群目前的治疗方法尚未得到充分服务。