Role of the purine nucleotide messengers cyclic ADP-ribose and ADP-ribose in T-lymphocyte biology

嘌呤核苷酸信使环状 ADP-核糖和 ADP-核糖在 T 淋巴细胞生物学中的作用

• 批准号: 86975855
• 负责人: Professor Dr. Andreas H. Guse
• 金额: --
• 依托单位: Institut für Biochemie und Signaltransduktion
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2009
• 资助国家: 德国
• 起止时间: 2008-12-31 至 2013-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/86975855?language=en
• 关键词: Role; purine; nucleotide; messengers; cyclic

P2X7 and TRPM2 are cation channels expressed by T lymphocytes that are gated by extra- and intracellular adenine nucleotides, respectively. P2X7, in addition, mediates membrane permeability changes towards multiple substrates including nucleotides and drugs. Although increasing evidence points to a pivotal role of both channels in inflammation, their effects on T cells remain unclear. The primary goal of the current project is thus to characterize the roles of P2X7 and TRPM2 during the early events of T cell activation. To this end, we will use live cell Ca2+ and ATP imaging, HPLC, and patch-clamp techniques to study the roles of these channels in TCR signaling. Especially, we will test the hypothesis that 2`-deoxy-adenosine diphosphoribose (2´-deoxy-ADPR), instead of ADPR, is the major endogenous activating ligand of TRPM2, and characterize P2X7-induced changes in T cell permeability to nucleotides and other signaling molecules, thereby providing a link between the worlds of signaling by intra- and extracellular nucleotides. Characterization of the roles of P2X7 and TRPM2 in TCR signaling will provide the basis for assessing the potential of new therapeutic strategies aimed at targeting these two ion channels.

P2 X7和TRPM 2是由T淋巴细胞表达的阳离子通道，分别由细胞外和细胞内腺嘌呤核苷酸门控。此外，P2 X7介导膜对包括核苷酸和药物在内的多种底物的渗透性变化。虽然越来越多的证据表明这两种通道在炎症中起着关键作用，但它们对T细胞的影响仍不清楚。因此，本项目的主要目标是表征P2 X7和TRPM 2在T细胞活化早期事件中的作用。为此，我们将使用活细胞Ca 2+和ATP成像，HPLC和膜片钳技术来研究这些通道在TCR信号传导中的作用。特别是，我们将测试的假设，2 '-脱氧-腺苷二磷酸核糖（2'-脱氧-ADPR），而不是ADPR，是TRPM 2的主要内源性激活配体，并表征P2 X7诱导的T细胞渗透性的变化，核苷酸和其他信号分子，从而提供了一个由内和胞外核苷酸的信号世界之间的联系。P2 X7和TRPM 2在TCR信号传导中的作用的表征将为评估旨在靶向这两种离子通道的新治疗策略的潜力提供基础。