Role of pro- and anti-inflammatory NF-κB and MAPK signaling of innate dendritic cells during asthma development in childhood and its modulation through farm environmental exposure

本项目旨在阐明炎症调节（NF-κB和MAPK信号）在儿童哮喘发展中免疫成熟过程中的作用及其通过环境刺激的保护作用。来自两个出生队列和一个横断面队列儿童的几个时间点的血液样本，这些儿童有哮喘风险或受哮喘保护，为检查哮喘发展的免疫机制提供了独特的机会。我们感兴趣的两个中心机制是免疫成熟过程中的促炎和抗炎途径，以及如何调节这些途径以预防儿童哮喘的发展。由于两个中心通路NF-κB和mapk信号传导是炎症的关键，我们将确定这些通路在分离的树突状细胞（DC）中的特定作用，在健康免疫成熟的不同阶段，树突状细胞对首次抗原接触很重要。此外，我们将分析当儿童患哮喘时，这些信号通路和dc亚群是否受到不同的调节。我们将在几个阶段检查这些途径，即在哮喘症状出现之前，在早期症状阶段和哮喘的慢性阶段。通过对炎症和免疫成熟网络应用最先进的机器学习算法，我们的目标是确定它们是如何连接和调节在一起的。此外，我们的目标是用新的分析工具定义健康炎症和成熟的窗口。应用原理验证实验，我们的目标是通过DC- t细胞共培养实验，通过实验调节健康和哮喘儿童的炎症条件（诱导离体DC中的促炎和抗炎条件）。为了发展哮喘发展的预防概念，我们的目标是解开一个名为训练免疫的新概念在环境介导的哮喘保护中的作用。为了实现这一目标，我们将研究先天免疫细胞的细胞特异性抗炎调节，研究转录机制的变化，并通过环境暴露检查表观遗传修饰。最后，我们的目标是确定一个“体内证明模型”，即评估炎症阈值和训练免疫。该项目不仅将解开哮喘发展的促炎和抗炎机制，而且还代表了一个独特的机会来解剖环境介导的儿童哮喘保护机制如何实施。这对未来针对哮喘和过敏的预防策略的转化研究至关重要。

This project aims to disentangle the role of inflammatory regulation (NF-κB and MAPK signalling) during immune maturation in childhood asthma development and its protection via environmental stimulation. Having blood samples from several time points of two birth cohorts and one cross-sectional cohort of children, which are at risk for asthma or protected from asthma offers a unique opportunity to examine immune mechanisms of asthma development. Two central mechanisms of interest are pro- and anti-inflammatory pathways during immune maturation and how these can be modulated in order to prevent the development of childhood asthma.As the two central pathways NF-κB and MAPK-signalling are key for inflammation, we will identify the specific role of these pathways in isolated dendritic cells (DC), important for first antigen-contact, at distinct stages of healthy immune maturation. Furthermore, we will dissect whether these signalling pathways and subpopulations of DCs are differently regulated when a child gets asthma. We will examine these pathways at several stages, namely prior to asthma symptoms, during the early symptomatic phase and during a chronic phase of asthma. By applying State-of-the-art machine learning algorithms for networks of inflammation and immune maturation, we aim to identify how they are connected and regulated together. Also, we aim to define a window of healthy inflammation and maturation with novel analysis tools. Applying a proof-of principle experiment, we aim to experimentally modulate inflammatory conditions (induction of pro- and anti- inflammatory conditions in isolated DC) of healthy and asthmatic children by DC-T-cell co-culture experiments.In order to develop preventive concepts for asthma development, we aim to disentangle the role of a novel conception named trained immunity in environment-mediated asthma protection. To achieve this, we will examine cell-specific anti-inflammatory regulation of innate immune cells, investigate changes in the transcriptional machinery and examine epigenetic modification via environmental exposure. Finally, we aim to identify a “model of in vivo proof”, namely to assess an inflammatory threshold and trained immunity.This project will not only disentangle pro- and anti-inflammatory mechanisms of asthma development, but also represents a unique opportunity to dissect mechanisms how environment-mediated protection against childhood asthma can be implemented. This is critical for future translational studies for preventive strategies against asthma and possibly allergies.