Ceramide kinase and its contribution to inflammatory and proliferative kidney diseases

神经酰胺激酶（CerK）是产生神经酰胺-1-磷酸（C1P）的酶，C1P是一种尚不明确的第二信使，被认为具有某些细胞功能，如进入前列腺素级联反应和参与细胞增殖。在这个项目中，我们计划研究这种鞘脂来源的介质在炎症性和增生性肾脏疾病中的信号传导能力。特别是，我们将解决(1)磷酸化反应对体外和完整肾细胞中CerK活性的影响，并鉴定相关的蛋白激酶。此外，我们将研究(2)肾细胞（包括肾小球系膜细胞、足细胞和肾母细胞肿瘤细胞）中CerK表达的调控，并通过使用酶的药理学抑制剂、消耗研究和研究CerK缺陷小鼠来揭示其对促炎和增殖细胞反应的贡献。最后，这些细胞培养实验将通过慢性炎症性肾病动物模型的体内研究来补充(3)。总之，这些研究将阐明CerK是否可以作为治疗炎症性和增生性肾脏疾病的新的治疗靶点。

Ceramide kinase (CerK) is the responsible enzyme for the generation of ceramide-1-phosphate (C1P) which is a still ill defined second messenger that has been attributed certain cellular functions such as feeding into the prostaglandin cascade and participating in cell proliferation. In this project we plan to investigate the signalling capacity of this sphingolipid-derived mediator in the setting of inflammatory and proliferative kidney diseases. Especially, we will address (1) the impact of phosphorylation reactions on CerK activity in vitro and in intact renal cells and identify the relevant protein kinases. Furthermore, we will study (2) the regulation of CerK expression in renal cells including glomerular mesangial cells, podocytes and Wilms tumor cells, and unravel its contribution to proinflammatory and proliferative cell responses by using a pharmacological inhibitor of the enzyme, by depletion studies, and by investigating CerK deficient mice. Finally, these cell culture experiments will be complemented (3) by in vivo studies on animal models of chronic inflammatory kidney diseases. In summary, these studies will clarify whether the CerK could serve as a new therapeutic target in the treatment of inflammatory and proliferative kidney diseases.