Epigenetic mechanisms of inflammatory memory propagation in human airway epithelia

人气道上皮炎症记忆传播的表观遗传机制

• 批准号: 10616766
• 负责人: Alejandro Antonio Pezzulo
• 金额: $ 56.09万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-05 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10616766
• 关键词: Acute; Address; Affect; Air; Airway Disease; Anti-Inflammatory Agents; Area; Asthma; Basal Cell; Biological Markers; Cause of Death; Cells; Chromatin; Chronic; Chronic Bronchitis; Data; Development; Disease; Disease susceptibility; Drug Targeting; Environment; Epigenetic Process; Epithelium; Failure; Genetic; Genetic Transcription; Goals; Goblet Cells; HSP 90 inhibition; Health; Hospitalization; Human; IL17 gene; Immune; Immune system; Immunologic Memory; In Vitro; Individual; Inflammation; Inflammatory; Inhalation; Ion Transport; Life; Liquid substance; Lung; Lung diseases; Memory; Metaplasia; Mission; Mitotic; Modification; Mucous body substance; National Heart, Lung, and Blood Institute; Nose; Persons; Phenotype; Predisposition; Production; Pulmonary Inflammation; Quality of life; Research; Resistance; Respiratory Failure; Severities; Smoking; TNF gene; Testing; Tracheobronchial; Translating; Virus; airway epithelium; airway inflammation; asthmatic; biobank; cell type; chronic inflammatory lung disease; clinical practice; curative treatments; cytokine; epigenetic memory; epigenome; epigenomics; improved; in vivo; inflammatory lung disease; innate immune function; inter-individual variation; memory acquisition; microorganism; mucus hypersecretion; novel; particle; postmitotic; precision medicine; resilience; response; stem cells; therapeutic target; transcriptome; transcriptomics

PROJECT SUMMARY / ABSTRACT Asthma and chronic bronchitis are among the top causes of death and hospitalizations worldwide. Chronic airway inflammation in asthma causes goblet cell metaplasia (GCM), mucus hypersecretion, and airway plugging, resulting in respiratory failure and poor quality of life. The mechanism for acquisition and persistence of chronic inflammation is not known. Current anti-inflammatory treatments for asthma can be ineffective and are not curative; chronic GCM resumes upon treatment discontinuation. Therefore, there is an urgent need to understand the mechanisms of chronic inflammation and GCM in asthma. Host genetics and the environment both contribute to asthma; the environment contributes to asthma by inducing immune and airway epithelial epigenetic memory. Basal stem cells in the airway epithelium may acquire epigenetic changes and act as a memory reservoir; as cellular turnover in the lungs occurs, basal cells replenish the epithelium and may propagate inflammatory memory, causing GCM. The importance of airway epithelial epigenetic memory in chronic lung inflammation is an emerging area of research. The central hypothesis of this proposal is that basal stem cells acquire IL-13-induced epigenetic changes and propagate inflammatory memory as they mitotically replenish the epithelium causing GCM and abnormal epithelial function; we plan to address the following aims: Specific Aim 1: Identify mechanisms of IL-13-induced memory in human large and small airway epithelia basal cells using transcriptomic, epigenomic, and clonotype analysis; we will determine the effect of IL-13-induced memory on GCM and function of airway epithelia. Specific Aim 2: Determine epigenetic inflammatory memory in asthmatic nasal airway basal cells obtained non- invasively using nasal brushings and in vitro expansion; this will allow us to determine how memory acquired by basal cells in asthma contribute to GCM, and whether inflammatory memory in asthma is IL-13- driven. Specific Aim 3: Investigate whether epigenetic changes acquired by tracheobronchial airway basal cells in vivo determine response to IL-13 in vitro leveraging a biobank of primary tracheobronchial basal cells developed by the PI; we will determine the epigenetic, transcriptional and phenotypic memory of epithelia highly susceptible to and epithelia resistant to IL-13-induced GCM. We will also determine whether drugs targeting GCM revert epigenetic memory. With the completion of this proposal, we expect to have identified A) novel mechanisms, B) treatment targets, and C) biomarkers and precision medicine strategies in asthmatics and other chronic inflammatory lung diseases. This is a first step to enable curative asthma treatments. We will further the NHLBI’s mission to “translate basic discoveries into clinical practice” and to “enhance the health of all individuals so that they can live longer and more fulfilling lives.”

项目概要/摘要 哮喘和慢性支气管炎是全世界死亡和住院的主要原因之一。 哮喘中的慢性气道炎症会导致杯状细胞化生 (GCM)、粘液分泌过多和 气道堵塞，导致呼吸衰竭和生活质量下降的机制。 目前对于哮喘的抗炎治疗是否持续存在尚不清楚。 无效且无法治愈；慢性 GCM 在治疗停止后会恢复。 迫切需要了解哮喘中慢性炎症和 GCM 的机制。 和环境都会导致哮喘；环境通过诱导免疫而导致哮喘。 气道上皮中的基底干细胞可能获得表观遗传记忆。 变化并充当记忆库；当肺部细胞发生更新时，基底细胞会补充 上皮细胞并可能传播炎症记忆，引起 GCM 气道上皮细胞的重要性。 慢性肺部炎症的表观遗传记忆是一个新兴研究领域的中心假设。 该提议认为基底干细胞获得 IL-13 诱导的表观遗传变化并传播炎症 记忆，因为它们会补充上皮细胞，导致 GCM 和我们计划的异常上皮功能； 实现以下目标： 具体目标 1：确定 IL-13 诱导人类记忆的机制 我们使用转录组、表观基因组和克隆型分析对大和小气道上皮基底细胞进行分析； 将确定 IL-13 诱导的记忆对 GCM 和气道上皮功能的影响。 2：确定非获得的哮喘鼻气道基底细胞的表观遗传炎症记忆 侵入性地使用鼻刷和体外扩张，这将使我们能够确定记忆是如何进行的； 哮喘中基底细胞获得的IL-13-有助于GCM，哮喘中的炎症记忆是否是IL-13- 具体目标 3：调查气管支气管气道是否发生表观遗传变化。 利用初级气管支气管的基础生物库，体内细胞确定体外对 IL-13 的反应 PI 发育的细胞；我们将确定其表观遗传、基础转录和表型记忆 我们还将确定是否对 IL-13 诱导的 GCM 高度敏感和耐药。 随着这项提案的完成，我们预计将有针对 GCM 的药物恢复表观遗传记忆。 确定了 A) 新机制，B) 治疗目标，以及 C) 生物标志物和精准医疗策略 这是治疗哮喘的第一步。 我们将进一步推进 NHLBI 的“将基本发现转化为临床实践”的使命。 “增强所有人的健康，使他们能够活得更长久、更充实的生活。”