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

基本信息

  • 批准号:
    10616766
  • 负责人:
  • 金额:
    $ 56.09万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 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

项目摘要

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.”
项目总结/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。 哮喘中的慢性气道炎症引起杯状细胞化生(GCM)、粘液分泌过多, 气道堵塞,导致呼吸衰竭和生活质量差。采购机制和 慢性炎症的持续性尚不清楚。目前哮喘的抗炎治疗方法可以是 无效且不能治愈;慢性GCM在治疗停止后恢复。因此有 迫切需要了解慢性炎症和GCM在哮喘中的机制。宿主遗传学 和环境都对哮喘起作用;环境通过诱导免疫系统而对哮喘起作用。 和气道上皮表观遗传记忆。气道上皮中的基底干细胞可能获得表观遗传的 变化,并作为一个记忆库;作为细胞周转在肺部发生,基底细胞补充 上皮,并可能传播炎症记忆,引起GCM。气道上皮细胞的重要性 慢性肺部炎症中的表观遗传记忆是一个新兴的研究领域。的中心假设 这一观点认为,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,因为他们有丝分裂补充上皮细胞引起GCM和异常上皮功能;我们计划 具体目的1:确定IL-13诱导的人类记忆的机制 使用转录组学、表观基因组学和克隆型分析, 将确定IL-13诱导的记忆对GCM和气道上皮功能的影响。具体目标 2:确定哮喘鼻气道基底细胞中的表观遗传炎症记忆,所述基底细胞获得非- 侵入性地使用鼻刷和体外扩张;这将使我们能够确定记忆如何 哮喘中基底细胞获得的炎症记忆对GCM的影响,以及哮喘中炎症记忆是否是IL-13- 有动力。具体目标3:研究气管支气管气道获得的表观遗传变化是否 利用原发性气管支气管炎的生物库,体内基底细胞在体外确定对IL-13的应答 PI开发的基底细胞;我们将确定表观遗传,转录和表型记忆, 对IL-13诱导的GCM高度敏感的上皮和对IL-13诱导的GCM抵抗的上皮。我们还将确定 针对GCM的药物可以逆转表观遗传记忆。随着这项建议的完成,我们预计 确定了A)新的机制,B)治疗靶点,以及C)生物标志物和精准医学策略 哮喘和其他慢性炎症性肺病。这是治疗哮喘的第一步 治疗。我们将进一步推进NHLBI的使命,“将基本发现转化为临床实践”, “增强所有人的健康,使他们能够活得更长,更充实。”

项目成果

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Alejandro Antonio Pezzulo其他文献

Alejandro Antonio Pezzulo的其他文献

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{{ truncateString('Alejandro Antonio Pezzulo', 18)}}的其他基金

Heat-shock protein 90 modulates goblet cell metaplasia in human airway epithelia
热休克蛋白 90 调节人气道上皮杯状细胞化生
  • 批准号:
    10359053
  • 财政年份:
    2019
  • 资助金额:
    $ 56.09万
  • 项目类别:
Heat-shock protein 90 modulates goblet cell metaplasia in human airway epithelia
热休克蛋白 90 调节人气道上皮杯状细胞化生
  • 批准号:
    10549769
  • 财政年份:
    2019
  • 资助金额:
    $ 56.09万
  • 项目类别:
Heat-shock protein 90 modulates goblet cell metaplasia in human airway epithelia
热休克蛋白 90 调节人气道上皮杯状细胞化生
  • 批准号:
    10089478
  • 财政年份:
    2019
  • 资助金额:
    $ 56.09万
  • 项目类别:

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