Novel inhibitors of neutral and acid ceramidases and their application in experimental therapies of inflammatory and proliferative kidney diseases

新型中性和酸性神经酰胺酶抑制剂及其在炎症和增殖性肾病实验治疗中的应用

• 批准号: 173771075
• 负责人: Professor Dr. Christoph Arenz
• 金额: --
• 依托单位: Arbeitsgruppe Organische und Bioorganische Chemie
• 依托单位国家: 德国
• 项目类别: Priority Programmes
• 财政年份: 2010
• 资助国家: 德国
• 起止时间: 2009-12-31 至 2013-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/173771075?language=en
• 关键词: Novel; inhibitors; neutral; acid; ceramidases

The cellular equilibrium between ceramide and sphingosine-1-phosphate plays a key role in functional cellular responses like cell differentiation, cell growth and cell death as well as in some aspects of inflammatory events. This cellular “sphingolipid rheostat” is primarily regulated by three classes of enzymes: The ceramide generating sphingomyelinases, the ceramide degrading ceramidases and finally the sphingosine kinases. Our aim is to develop and synthesize novel inhibitors of the different ceramidases. We plan to test the substances in in vitro tests using recombinant human and murine enzymes. Afterwards, the cellular activity will be assessed with regards on cellular ceramidase activites, on cellular lipid concentrations and on cellular responses like cell-proliferation and apoptosis. Glomerulonephritis is a chronic inflammatory kidney disease in which hyperproliferation is an important aspect. We plan to test novel ceramidase inhibitors in cellular assays for inflammatory and hyperproliferative kidney diseases, but also in cancer cells. Finally promising candidates will be used for experimental therapies employing cellular and in vivo models of glomerulonephritis and cancer.

神经酰胺和鞘氨醇-1-磷酸之间的细胞平衡在细胞分化、细胞生长和细胞死亡等功能性细胞反应以及炎症事件的某些方面起着关键作用。这种细胞“鞘脂变阻器”主要由三类酶调节：生成鞘磷脂酶的神经酰胺，降解神经酰胺酶的神经酰胺，最后是鞘磷脂激酶。我们的目标是开发和合成不同神经酰胺酶的新型抑制剂。我们计划在体外测试中使用重组人类和小鼠酶来测试这些物质。之后，将对细胞活性进行评估，包括细胞神经酰胺酶活性、细胞脂质浓度以及细胞增殖和凋亡等细胞反应。肾小球肾炎是一种慢性炎症性肾脏疾病，其中增生是一个重要方面。我们计划在炎症性和增生性肾脏疾病的细胞检测中测试新型神经酰胺酶抑制剂，也在癌细胞中测试。最后，有希望的候选药物将用于肾小球肾炎和癌症的细胞和体内模型的实验治疗。