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

通过使用人类白细胞的离体研究开发拮抗性胸腺基质淋巴细胞生成素 (TSLP) 变体并评估其对哮喘相关 TSLP 活性的抑制特性

• 批准号: 388835396
• 负责人: Professor Dr. Karlheinz Friedrich
• 金额: --
• 依托单位: Zentrum für Innere Medizin
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2017
• 资助国家: 德国
• 起止时间: 2016-12-31 至 2020-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/388835396?language=en
• 关键词: Development; antagonistic; Thymic; Stromal; Lymphopoietin

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.

毛细支气管炎是最常见的慢性病之一，发病率呈上升趋势。细胞因子胸腺基质淋巴细胞生成素(TSLP)及其受体TSLPR(根据目前的模型是TSLP受体α链和IL-7受体α链的异源二聚体)在过敏性哮喘的发病机制中起重要作用。因此，该系统是特定抑制物质的一个有吸引力的目标。在这个项目中，根据小鼠TSLPR的结构模型设计，与野生型细胞因子相比，具有潜在拮抗/抑制特性的人TSLP变体将被重组生产，并在细胞模型系统中进行表征。TSLP受体系统的激活机制还不是很清楚。因此，将从生物化学(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体)进行表征，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。潜在抑制剂的特性和应用潜力将在原代人肺细胞上进行体外测试。这些研究将特别关注TSLP反应性髓系树突状细胞和嗜碱性粒细胞。

项目成果

A versatile platform for activity determination of cytokines and growth factors based on the human TSLP (thymic stromal lymphopoietin) receptor

基于人 TSLP（胸腺基质淋巴细胞生成素）受体的细胞因子和生长因子活性测定的多功能平台

• DOI: 10.1016/j.cyto.2018.07.010
• 发表时间: 2019
• 期刊: Cytokine
• 影响因子: 3.8
• 作者: Marković I;Barthel T;Schirmer M;Gonzälez Delgado A;Wilhelm S;Krause S;Friedrich K;Wohlmann A
• 通讯作者: Wohlmann A

FACS-Based Functional Protein Screening via Microfluidic Co-encapsulation of Yeast Secretor and Mammalian Reporter Cells

• DOI: 10.1038/s41598-020-66927-5
• 发表时间: 2020-06-23
• 期刊: SCIENTIFIC REPORTS
• 影响因子: 4.6
• 作者: Yanakieva, Desislava;Elter, Adrian;Kolmar, Harald
• 通讯作者: Kolmar, Harald