The role of Cdc-like kinase 2 (Clk2) in hepatic glucose and lipid metabolism

胰岛素抵抗(IR)在代谢综合征的病理生理学中起着至关重要的作用。非酒精性脂肪性肝病(NAFLD)是这种疾病的早期和突出的标志。因此，IR触发了信号转导通路的改变，包括糖脂代谢和慢性终末期肝硬变和肝细胞癌的肝损伤的发展。在我们之前的工作中，我们已经剖析了参与肝脏炎症、NAFLD、肝硬变和肝细胞癌发展的分子通路。我目前的目标是深化导致糖尿病和代谢综合征等代谢紊乱的肝内信号通路。主办机构在分子代谢、系统生物学和相关代谢物领域拥有杰出的专业知识。最近，CDC样激酶2(Clk2)在肝脏糖代谢中的作用被描述和发表。Clk2受到高度调控，取决于细胞的能量状态。转录共激活因子PGC1-α被Clk2磷酸化，导致肝脏糖异生减少。PGC1-α构象状态的变化会影响其与PPAR-α的相互作用。因此，PGC1-α可能在脂肪酸氧化和脂类代谢中具有潜在作用。然而，这一规定的确切机制仍然难以捉摸。主办机构将提供多种技术解决方案和转基因小鼠模型，分别允许调节Clk2的活性及其底物PGC1-α。本提案的最终目的是阐明Clk2的作用及其与PGC1-α在不同代谢条件下的相互作用，如禁食、进食和糖尿病。主办机构将提供这一研究领域的广泛知识。该项目将帮助申请者进一步发展他在信号转导和新陈代谢领域的技能，将这些知识传授给RWTH亚琛。

Insulin resistance (IR) plays a crucial role in the pathophysiology of the metabolic syndrome. Non- alcoholic fatty liver disease (NAFLD) is an early and prominent hallmark of this disease. As a consequence, IR triggers changes in signal transduction pathways, including glucose and lipid metabolism and the development of liver injury to chronic end-stage cirrhosis and HCC. In our previous work, we have dissected the molecular pathways involved in liver inflammation, NAFLD, liver cirrhosis and HCC development. My current aim is to deepen in the intrahepatic signaling pathways which lead to metabolic disorders such as diabetes and metabolic syndrome.The host institution possesses an outstanding expertise in the field of molecular metabolism, systems biology and related metabolites. Recently, the role of the Cdc-like Kinase 2 (Clk2) in hepatic glucose metabolism was described and published. Clk2 is highly regulated depending on the cellular energy state. PGC1-alpha , a transcription coactivator, is phosphorylated by Clk2 leading to a decrease of hepatic gluconeogenesis. Changes in the conformational state of PGC1- alpha affect its interaction with PPAR-alpha. Thus PGC1-alpha might have a potential role in fatty acid oxidation and lipid metabolism. However, the precise mechanism of this regulation remains elusive. The host institution will provide a wide variety of technical solutions and transgene mouse models allowing the modulation of Clk2 activity and its substrate PGC1-alpha, respectively.The final aim of the present proposal is to elucidate the role of Clk2 and its interaction with PGC1-alpha in different metabolic conditions such as Fasting, Feeding and Diabetes. The host institution will provide broad knowledge in this field of research. The project will help the applicant to further develop his skills in the field of Signal Transduction and metabolism, transferring this knowledge to the RWTH Aachen.