Age-related mechanisms of T helper 2 memory in the early lung

早期肺部辅助T辅助细胞2记忆的年龄相关机制

• 批准号: 10653092
• 负责人: Xingbin Ai
• 金额: $ 53.95万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-09 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10653092
• 关键词: Address; Adoptive Transfer; Adrenergic Agents; Adult; Age; Age of Onset; Airway Disease; Allergens; Allergic inflammation; Alpha Interleukin 2 Receptor; Biological Assay; Birth; Brain-Derived Neurotrophic Factor; Bronchoconstriction; CD4 Positive T Lymphocytes; Cells; Childhood Asthma; Clinical Research; Communication; Complex; DRD4 gene; Dependovirus; Dopamine; Environment; Epigenetic Process; Extrinsic asthma; Fostering; Gene Delivery; Genetic Transcription; Histologic; Human; Inflammation; Interleukin-2; Intervention; Life; Link; Location; Long-Term Effects; Lung; Maps; Mediating; Mediator; Memory; Molecular Target; Neonatal; Nerve; Nerve Growth Factors; Ovalbumin; Pathogenesis; Pathway interactions; Patients; Pharmacologic Substance; Phenotype; Polycomb; Predisposition; Publishing; Recurrence; Recurrent disease; Reporting; Risk; Role; Severities; Signal Transduction; Stat5 protein; T-Lymphocyte; Testing; Viral; age related; airway inflammation; allergic response; asthmatic; candidate identification; chronic inflammatory disease; chronic respiratory disease; early childhood; early life exposure; empowerment; genetic approach; genetic signature; genome wide association study; in vivo; infancy; insight; lung development; mouse model; neonatal exposure; neonate; nerve supply; novel; novel therapeutics; overexpression; postnatal; postnatal development; receptor; transcription factor; transcriptomic profiling; transcriptomics; treatment strategy

PROJECT SUMMARY Allergic asthma is one of the most common, chronic airway diseases that often progresses from infancy and early childhood into adulthood. Current therapies are directed at antagonizing inflammation and bronchial constriction. Despite their widespread use, these therapies have no beneficial effect on slowing down the progression of allergic asthma. The central mediator of anamnestic allergic responses is allergen-specific, T helper 2 resident memory cells (Th2-TRMs). As such, targeting the establishment of allergen-specific, Th2-TRMs following early life exposure provides an opportunity to modulate and impede progressive allergic asthma. However, how Th2-TRMs are established in the early lung has never been studied. To address this critical issue in the pathogenesis of progressive allergic asthma, we have investigated the causal link between allergen exposure in early life and the long-term effect on airway inflammation. Our study focuses on the communication between sympathetic nerves and CD4+ T cells in the postnatal, developing lung. So far, our published and preliminary studies have identified a significant role of nerve-derived dopamine in susceptibility to allergic asthma in early life and anamnestic allergic responses in adults. We show that dopamine signals through a T cell-specific DRD4 receptor to promote Th2-TRM phenotypes by activating transcriptional factors and epigenetic modulators in Th2 cells. Interestingly, sympathetic nerves transition into an adrenergic phenotype with age. Therefore, nerve- derived dopamine operates in an age-related manner to promote Th2 memory. Given the critical role of dopamine in the establishment of Th2-TRMs in the early lung, we have investigated the postnatal development of sympathetic nerves. We found an age-related reduction in the levels of nerve growth factor (NGF) and brain- derived neurotrophic factor (BDNF) that was associated with the dopaminergic-to-adrenergic transition of sympathetic nerves. Empowered by these preliminary findings, we propose the central hypotheses: dopamine promotes the establishment of allergen-specific, Th2-TRMs in the early lung; the dopaminergic-to- adrenergic transition of sympathetic nerves is caused by age-related reduction in NGF and BDNF levels. These hypotheses will be tested by the following three specific aims. Aim 1 will define the specific role of dopamine in the abundance and the function of allergen-specific, Th2-TRMs following allergen exposure in early life. Aim 2 will identify functional mediators of dopamine signaling in Th2-TRM phenotypes. Aim 3 will determine the role of NGF and BDNF in sympathetic innervation and allergen-specific, Th2-TRMs in the lung. Of note, clinical studies and GWAS have reported positive correlation between the levels of NGF and BDNF and allergic asthma. Taken together, our proposed studies will provide insights into the establishment of Th2-TRMs in the early lung and identify molecular targets for the intervention of progressive asthma from childhood to adulthood.

项目摘要 过敏性哮喘是最常见的慢性气道疾病之一，通常从婴儿期和 幼儿到成年。当前疗法针对拮抗炎症和支气管 收缩。尽管它们广泛使用，但这些疗法对放慢脚步没有任何有益的影响 过敏性哮喘的进展。厌氧过敏反应的中心介质是过敏原特异性的，t 辅助2驻留记忆单元（TH2-TRM）。因此，针对过敏原特异性Th2-TRM的建立 随后，生命早期暴露提供了一个机会，以调节和阻碍进步性过敏性哮喘。 但是，从未研究过如何在早期肺中建立Th2-TRM。解决这个关键问题 在进行性过敏性哮喘的发病机理中，我们研究了过敏原之间的因果关系 早期生活和对气道炎症的长期影响。我们的研究重点是交流 在产后，发育肺的交感神经和CD4+ T细胞之间。到目前为止，我们已发布 初步研究已经确定了神经衍生的多巴胺在对过敏性哮喘的敏感性中的重要作用 在早期生命和成年人的厌氧过敏反应中。我们证明了通过T细胞特异性的多巴胺信号 DRD4受体通过激活转录因子和表观遗传调节剂来促进Th2-TRM表型 在Th2细胞中。有趣的是，随着年龄的增长，交感神经过渡到肾上腺素能表型。因此，神经 - 衍生的多巴胺以年龄相关的方式运行以促进Th2记忆。考虑到多巴胺的关键作用 在早期肺部建立Th2-TRM时，我们已经调查了产后的发展 交感神经。我们发现神经生长因子（NGF）和大脑的水平与年龄有关的降低 衍生的神经营养因子（BDNF），与多巴胺能到肾上腺素能的过渡有关 交感神经。通过这些初步发现的能力，我们提出了中心假设：多巴胺 促进在早期肺部建立过敏原特异性Th2-TRM；多巴胺能到 - 交感神经的肾上腺素能过渡是由年龄相关的NGF和BDNF水平降低引起的。 这些假设将通过以下三个特定目标进行检验。 AIM 1将定义特定角色 在过敏原暴露后，多巴胺在过敏原特异性的Th2-TRM的功能中 生活。 AIM 2将识别Th2-TRM表型中多巴胺信号传导的功能介体。 AIM 3将确定 NGF和BDNF在肺中Th2-Trms的交感神经神经和过敏原特异性的作用。值得注意的是， 临床研究和GWAS报告了NGF和BDNF水平与过敏性之间的正相关 哮喘。综上所述，我们拟议的研究将提供有关建立Th2-TRM的见解 早期肺并确定从儿童期到成年的进行性哮喘干预的分子靶标。