Sphingosylphosphorylcholine and its contribution to pathophysiological processes in the kidney

鞘氨醇磷酸胆碱（SPC）与1-磷酸鞘氨醇（S1 P）和溶血磷脂酰胆碱（LPC）具有结构相似性，并且同样能够与G蛋白偶联受体（GPCR）的子集结合，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。该项目旨在确定参与的SPC受体，这些受体有助于肾细胞的抗炎和促纤维化反应。将特别关注结合鞘脂的GPCR与具有丝氨酸/苏氨酸激酶活性的受体（如TGFβ受体）之间的串扰，从而突出GPCR触发的受体转调节的另一个病理生理相关方面。从TGFβ在纤维化过程中的已知作用出发，我们将研究鞘脂触发的信号转导对基质调节酶如基质金属蛋白酶9、组织纤溶酶原激活物（tPA）及其内源性抑制剂TIMP和PAI的作用。此外，我们计划在肾脏的生理和病理生理条件下表征SPC的产生，并确定相关的SPC受体。在长期的基础上，将研究鞘脂（SPC和S1 P受体）特异性GPCR作为治疗纤维化肾病的潜在药理学靶点。

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.