Development of antagonistic Thymic Stromal Lymphopoietin (TSLP) variants and evaluation of their inhibitory properties towards asthma-associated TSLP activity by ex vivo studies employing human leukocytes

支气管哮喘是最常见的慢性疾病之一，发病率越来越高。细胞因子胸腺基质淋巴生成素（TSLP）及其受体TSLPR（根据目前的模型，TSLP受体α链和白细胞介素-7受体α链的异源二聚体）在过敏性哮喘的发病机制中起关键作用。因此，该系统是特定抑制物质的一个有吸引力的目标。在本项目中，基于小鼠TSLPR的结构模型设计，与野生型细胞因子相比，人类TSLP的变体具有潜在的拮抗/抑制特性，将在细胞模型系统中重组产生并表征。TSLP受体系统的激活机制尚不清楚。因此，它将被生物化学（从重组蛋白开始）和细胞生物学（基于报告细胞中功能表达的受体变异）表征，目的是为产生高亲和力和高效率的抑制剂开辟新的途径和分子策略。在体外原代人肺细胞上测试潜在抑制剂的特性和应用潜力。这些研究将特别关注TSLP反应性骨髓树突状细胞和嗜碱性粒细胞。

Asthma bronchiale is one of the most common chronic diseases with increasing prevalence. The cytokine Thymic Stromal Lymphopoietin (TSLP) and its receptor TSLPR (according to the current model a heterodimer of the TSLP receptor alpha-chain and the interleukin-7 receptor alpha-chain) are critically involved in the pathogenesis of allergic asthma. This system is therefore an attractive target for specific inhibitory substances. In this project, designed on the basis of a structural model of the murine TSLPR, variants of the human TSLP with potentially antagonistic / inhibitory properties compared to the wild-type cytokine, will be recombinantly produced and characterized in a cellular model system. The activation mechanism of the TSLP receptor system is not sufficiently well understood. It will be, hence, be characterized biochemically (starting from recombinant proteins) and cell biologically (based on functionally expressed receptor variants in reporter cells) with the aim of opening up novel routes and molecular strategies for the generation of inhibitors with high affinity and efficiency.The characteristics and the application potential of the potential inhibitors will be tested in vitro on primary human lung cells. These investigations will in particular focus on TSLP reactive myeloid dendritic cells and basophilic granulocytes.