Identification and characterization of pruritus pathways in chronic skin inflammation

慢性皮肤炎症中瘙痒途径的识别和表征

• 批准号: 399451442
• 负责人: Professor Dr. Bernhard Homey
• 金额: --
• 依托单位: Hautklinik
• 依托单位国家: 德国
• 项目类别: Research Units
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/399451442?language=en
• 关键词: Identification; characterization; pruritus; pathways; chronic

Identification and characterization of pruritus pathways in chronic skin inflammation: microbes as exogenous drivers of itchChronic pruritus is a major clinical complaint, has a high prevalence, severely reduces the quality of life and is difficult to treat. The main problem for the development of targeted therapies has been a lack of pathophysiologic concepts. The key objective of project #5 is the in-depth characterization of known (IL-31/IL-31RA) and the identification of novel pruritus pathways during chronic skin inflammation. We are investigating distinct skin diseases such as lichen planus (TH1), atopic dermatitis (TH2) and psoriasis (TH17) as “role models” of itch. During the first funding period, the applicants succeeded in recruiting atopic dermatitis, psoriasis and lichen planus patients as well as matching controls (total n=171) for a physical biomaterial collection. All individuals were clinically characterized, electrically stimulated and biomaterial (skin, PBMCs, plasma) was obtained further analyses. At this point, we identified a transcriptomic “pruritus signature” in atopic dermatitis patients. Furthermore, we defined IL-31-producing circulating cells as a subset of CLA+ CRTH2+ CCR4+ TH2 cells that belong to the effector memory population and demonstrated that IL-31 promotes the differentiation of plasmablasts in vivo. Moreover, we uncovered that basophils express TRPV1 and produce TSLP following IL-31 stimulation. In atopic dermatitis patients, we showed that the brain derived neurotrophic factor (BDNF) is released by eosinophils and induces neuronal growth. During the second funding period, the applicants will address the following aims: (1) Deep phenotyping of IL-31-producing cells; (2) unravel the relative contribution of distinct IL-31RA+ cell types to mediate barrier dysfunction, inflammation, neuronal growth and pruritus; (3) define and validate pruritus pathways in distinct chronic inflammatory skin diseases and (4) unravel the role of microbes as exogenous triggers of itch. The applicants will follow a common experimental path with (a) explore own or public datasets using bioinformatics, (b) further investigation using in vitro-models and (c) confirmation and validation of these findings in vivo. Along this path, we have pre-analyzed large own and public datasets, have obtained a significant bio-resource during the 1st period and will obtain more information from longitudinal analyses of transcriptomes as well as microbiomes in patients. Moreover, we will use state-of-the-art conditional knockout (Il31ra) and reporter (Il31) mouse models. Taken together, findings of this study will increase our understanding of pruritus pathways with an emphasis on understanding the role of IL-31RA signaling as well as of microbes as exogenous triggers of itch. It will define and validate biomarkers for chronic pruritus that may serve as therapeutic targets.

慢性皮肤炎症瘙痒途径的识别和表征：微生物作为瘙痒的外源性驱动因素慢性瘙痒是一种主要的临床症状，患病率高，严重降低生活质量，难以治疗。靶向治疗发展的主要问题是缺乏病理生理学概念。项目#5的关键目标是深入表征已知的（IL-31/IL-31 RA）并鉴定慢性皮肤炎症期间的新型瘙痒途径。我们正在研究不同的皮肤病，如扁平苔藓（TH 1），特应性皮炎（TH 2）和银屑病（TH 17）作为瘙痒的“角色模型”。在第一个资助期内，申请人成功招募了特应性皮炎、银屑病和扁平苔藓患者以及匹配的对照组（总计n=171），用于物理生物材料收集。对所有个体进行临床表征、电刺激并获得生物材料（皮肤、PBMC、血浆）进行进一步分析。在这一点上，我们确定了一个转录组学的“瘙痒签名”的特应性皮炎患者。此外，我们将产生IL-31的循环细胞定义为属于效应记忆群体的CLA+ CRTH 2 + CCR 4 + TH 2细胞的子集，并证明IL-31促进体内浆母细胞的分化。此外，我们发现，嗜碱性粒细胞表达TRPV 1和产生TSLP后IL-31刺激。在特应性皮炎患者中，我们发现脑源性神经营养因子（BDNF）由嗜酸性粒细胞释放并诱导神经元生长。在第二个资助期内，申请人将致力于以下目标：（1）IL-31产生细胞的深层表型分析;（2）阐明不同IL-31 RA+细胞类型对介导屏障功能障碍、炎症、神经元生长和瘙痒的相对贡献;（3）确定和验证不同慢性炎症性皮肤病中的瘙痒途径，以及（4）阐明微生物作为瘙痒的外源性触发因素的作用。申请人将遵循共同的实验路径，（a）使用生物信息学探索自己或公共数据集，（B）使用体外模型进行进一步研究，以及（c）在体内确认和验证这些发现。沿着这条道路，我们已经预先分析了自己和公共的大型数据集，在第一阶段获得了重要的生物资源，并将从患者的转录组和微生物组的纵向分析中获得更多信息。此外，我们将使用最先进的条件性敲除（Il 31 ra）和报告基因（Il 31）小鼠模型。 总之，这项研究的结果将增加我们对瘙痒途径的理解，重点是了解IL-31 RA信号传导的作用以及微生物作为瘙痒的外源性触发因素。它将定义和验证可能作为治疗靶点的慢性瘙痒症生物标志物。