Lipid regulation of T cell receptor transmembrane signaling

T 细胞受体跨膜信号传导的脂质调节

• 批准号: 410545195
• 负责人: Professor Dr. Wolfgang Schamel
• 金额: --
• 依托单位: Institut für Biologie III
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2019
• 资助国家: 德国
• 起止时间: 2018-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/410545195?language=en
• 关键词: Lipid; regulation; cell; receptor; transmembrane

T cell-based cancer immunotherapies have received unprecedented success in treating cancers but their efficacies and applications are still limited, which calls for more mechanistic studies of T cell activation. As a major receptor on the T cell surface, the T cell receptor (TCR) recognizes antigen and delivers the main activating signal to the cell. Previous works from the Xu and Schamel labs highlight the importance of membrane lipids in regulating TCR transmembrane signaling, but the underlying molecular mechanisms are not well understood. Here we plan to combine the expertise from both labs, using state-of-the-art imaging, nuclear magnetic resonance, sophisticated lipid biochemistry and disease models. With this cooperative project we aim to understand the spatiotemporal dynamics of cholesterol and sphingomeylin (SM) redistribution in the plasma membrane, the specific interactions between cholesterol, SM and TCR transmembrane (TM) domains, as well as the functional importance of these lipid-protein interactions. The performance of this project will lead to better understanding of the major signalling event in T cell, i.e. TCR transmembrane signalling, and might also lead to design more efficient chimeric antigen receptors (CARs) for cancer immunotherapy.

基于T细胞的癌症免疫疗法在治疗癌症方面取得了前所未有的成功，但其功效和应用仍然有限，这需要更多的T细胞活化机制研究。作为T细胞表面上的主要受体，T细胞受体（TCR）识别抗原并将主要活化信号递送至细胞。Xu和Schamel实验室以前的工作强调了膜脂质在调节TCR跨膜信号传导中的重要性，但其潜在的分子机制尚未得到很好的理解。在这里，我们计划联合收割机结合两个实验室的专业知识，使用最先进的成像，核磁共振，复杂的脂质生物化学和疾病模型。通过这个合作项目，我们的目标是了解质膜中胆固醇和鞘氨醇（SM）再分布的时空动态，胆固醇，SM和TCR跨膜（TM）结构域之间的特定相互作用，以及这些脂质-蛋白质相互作用的功能重要性。该项目的实施将导致更好地理解T细胞中的主要信号事件，即TCR跨膜信号传导，并且还可能导致设计用于癌症免疫治疗的更有效的嵌合抗原受体（汽车）。