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

项目总结 过敏性哮喘是最常见的慢性呼吸道疾病之一，通常从婴儿期和 从儿童早期到成年。目前的治疗方法是针对抗炎和哮喘。 收缩。尽管这些疗法得到了广泛的应用，但它们并没有对延缓 过敏性哮喘的进展。记忆性过敏反应的中心介质是过敏原特异性的T 辅助2驻留存储单元(Th2-TRMS)。因此，针对特定过敏原的Th2-TRMS的建立 早期接触提供了调节和阻止进行性过敏性哮喘的机会。 然而，Th2-TRMS是如何在早期肺中建立的还从未被研究过。要解决这一关键问题 在进行性过敏性哮喘的发病机制中，我们研究了过敏原与 生命早期暴露和对呼吸道炎症的长期影响。我们的研究重点是交际 交感神经和CD4T细胞之间，在出生后发育中的肺。到目前为止，我们出版的和 初步研究发现，神经源性多巴胺在过敏性哮喘易感性中起重要作用。 早期生活和成人的记忆过敏反应。我们发现多巴胺信号是通过T细胞特异性的 DRD4受体通过激活转录因子和表观遗传调节因子促进Th2-TRM表型 在Th2细胞中。有趣的是，交感神经随着年龄的增长而转变为肾上腺素能表型。因此，神经- 衍生的多巴胺以与年龄相关的方式发挥作用，以促进Th2记忆。鉴于多巴胺的关键作用 在早期肺Th2-TRMS的建立中，我们研究了小鼠出生后的发育。 交感神经。我们发现，随着年龄的增长，神经生长因子(NGF)和脑- 与多巴胺能向肾上腺素能转化相关的衍生神经营养因子(BDNF) 交感神经。根据这些初步发现，我们提出了以下中心假说：多巴胺 促进变应原特异性Th2-TRMS在早期肺中的建立；多巴胺能到... 交感神经的肾上腺素能转换是由年龄相关的NGF和BDNF水平降低引起的。 这些假设将通过以下三个具体目标进行检验。目标1将定义 早期变应原暴露后变应原特异性Th2-TRMS中的多巴胺含量和功能 生活。目的2将在Th2-TRM表型中确定多巴胺信号的功能介体。目标3将决定 NGF和BDNF在交感神经支配和肺内变应原特异性Th2-TRMS中的作用。值得注意的是， 临床研究和GWAS已报道NGF和BDNF水平与变态反应呈正相关 哮喘。综上所述，我们建议的研究将为在中国建立Th2-TRMS提供见解。 并确定干预从儿童到成年的进行性哮喘的分子靶点。

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.