Divergent E1 and E2 epithelial differentiation and associated regulatory mechanisms of IL-20 family members

IL-20家族成员的不同E1和E2上皮分化及相关调节机制

• 批准号: 398577603
• 负责人: Professor Dr. Carsten B. Schmidt-Weber, Ph.D.
• 金额: --
• 依托单位: Zentrum für Allergie und Umwelt (ZAUM)
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2018
• 资助国家: 德国
• 起止时间: 2017-12-31 至 2021-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/398577603?language=en
• 关键词: Divergent; E1; E2; epithelial; differentiation

Allergy affects 20% of the population with an increasing trend. The cause and in particular the mechanism of sensitization are yet unknown. Epithelial cells are playing an important role in this process as they are not only forming a barrier, but also contribute to the first context recognition when the antigen is entering the organism. So far, it was not known that epithelial cells undergo a differentiation that polarizes the cells either to a pro-allergic E2-type or an E2 type that is likely to be important for infections. This kind of phenotype imprinting was observed also for T cells or macrophages. Preliminary evidences suggest that this differentiation also modulates epithelial mechanisms of immune regulation, particularly those of the IL-20 family. This group of genes is suspected in anti-inflammatory responses and could be relevant for reconvalescense following airway inflammation. It is therefore a key objective of the research proposal to explore the epithelial differentiation mechanisms and also whether pluripotent epithelial precursor cells are affected, since these are relevant for the regeneration of the epithelial surface. In fact preliminary data suggest that E2 priming occurs on the basal cell level and that E2 priming is dramatically increased in basal cells of trachea of house dust mite sensitized mice. An impact on this level could have a sustained effect for affected patients. In addition the project wants to elucidate whether the distinct epithelial phenotypes give rise to differential responses to bacterial pathogens that are commonly playing a role in exacerbation of airways diseases such as asthma. The regulation of the IL-20 family is a focus of the study readouts as the mediators are thought to mediate epithelial recovery. Since the airway epithelium is well accessible for novel therapeutics, the proposed research can open novel therapeutic option for allergic airway diseases.

过敏症影响20%的人口，并呈上升趋势。致敏的原因，特别是致敏机制尚不清楚。上皮细胞在这一过程中发挥着重要作用，因为它们不仅形成屏障，而且还有助于抗原进入生物体时的第一次背景识别。到目前为止，还不知道上皮细胞经历分化，使细胞极化为促过敏E2型或可能对感染重要的E2型。这种表型印记也在T细胞或巨噬细胞中观察到。初步证据表明，这种分化也调节免疫调节的上皮机制，特别是IL-20家族的免疫调节机制。这组基因被怀疑在抗炎反应，并可能与气道炎症后的恢复有关。因此，研究提案的一个关键目标是探索上皮分化机制以及多能上皮前体细胞是否受到影响，因为这些与上皮表面的再生有关。事实上，初步的数据表明，E2引发发生在基底细胞水平上，并且在屋尘螨致敏小鼠的气管基底细胞中E2引发显著增加。对这一水平的影响可能对受影响的患者产生持续影响。 此外，该项目还希望阐明不同的上皮表型是否会引起对细菌病原体的不同反应，这些细菌病原体通常在哮喘等气道疾病的恶化中发挥作用。IL-20家族的调节是研究读数的焦点，因为介质被认为介导上皮恢复。由于气道上皮是很容易获得的新疗法，拟议的研究可以打开新的治疗选择过敏性气道疾病。