Sphingosylphosphorylcholine and its contribution to pathophysiological processes in the kidney

鞘氨醇磷酰胆碱及其对肾脏病理生理过程的贡献

• 批准号: 39666547
• 负责人: Professor Dr. Josef M. Pfeilschifter
• 金额: --
• 依托单位: Institut für Pharmakologie
• 依托单位国家: 德国
• 项目类别: Priority Programmes
• 财政年份: 2007
• 资助国家: 德国
• 起止时间: 2006-12-31 至 2010-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/39666547?language=en
• 关键词: Sphingosylphosphorylcholine; its; contribution; pathophysiological; processes

Sphingosylphosphorylcholine (SPC) shows structural similarities to both sphingosine 1- phosphate (S1P) and lysophosphatidylcholine (LPC), and is similarly able to bind to a subset of G protein-coupled receptors (GPCRs) to finally trigger responses such as cell proliferation, vessel contraction or dilatation, and modulation of inflammatory and fibrotic processes. This project aims in identifying the involved SPC receptors that contribute to an anti-inflammatory and pro-fibrotic response of renal cells. A special focus will be put on the crosstalk between GPCRs binding sphingolipids and receptors with serine/threonine kinase activity like the TGFβ receptor, thus highlighting an additional pathophysiologically relevant facet of GPCR-triggered receptor transmodulation. Starting from the known effects of TGFβ on fibrotic processes we will investigate the role of sphingolipid-triggered signal transduction on matrixregulating enzymes, such as matrix metalloproteinase-9, tissue plasminogen activataor (tPA) and their endogenous inhibitors TIMPs and PAIs. Furthermore, we plan to characterize the generation of SPC during physiological and pathophysiological conditions in the kidney and to identify the relevant SPC receptors. On a long-term basis GPCRs specific for sphingolipids (SPC and S1P receptors) will be investigated as potential pharmacological targets to treat fibrotic renal diseases.

sphingosylphospylcholine （SPC）与sphingosine 1- phosphate （S1P）和lysophosphatidycholine （LPC）具有相似的结构，并且能够与G蛋白偶联受体（gpcr）结合，最终触发细胞增殖、血管收缩或扩张以及炎症和纤维化过程的调节等反应。本项目旨在确定参与抗炎和促纤维化肾细胞反应的SPC受体。将特别关注gpcr结合鞘脂和具有丝氨酸/苏氨酸激酶活性的受体（如TGFβ受体）之间的串扰，从而强调gpcr触发的受体转调的另一个病理生理相关方面。从已知的TGFβ在纤维化过程中的作用出发，我们将研究鞘脂触发的信号转导对基质调节酶的作用，如基质金属蛋白酶-9、组织纤溶酶原激活物（tPA）及其内源性抑制剂TIMPs和PAIs。此外，我们计划在肾脏的生理和病理生理条件下描述SPC的产生，并确定相关的SPC受体。在长期的基础上，鞘脂（SPC和S1P受体）特异性的gpcr将被研究作为治疗纤维化肾脏疾病的潜在药理靶点。