Role of Ubiquitin C-Terminal Hydrolase-L1 in Glomerulonephritis

泛素C末端水解酶-L1(UCH-L1)是泛素系统中的关键分子，通过单体泛素的产生和稳定发挥作用。此前，我们在细胞培养实验、活体实验和人类肾小球疾病中证明了UCH-L1在肾小球疾病期间调节足细胞中泛素的稳态。在第一部分，我们想要分析UCH-L1在足细胞损伤中的确切功能。因此，我们建立了足细胞选择性UCH-L1基因缺陷小鼠，以诱导足细胞损伤的免疫学和毒性模型，并随后评估足细胞损伤的临床和形态学参数。UCH-L1缺乏和突变的生化效应将在足细胞培养实验中进行分析。在第二部分中，我们将评估UCH-L1在人类膜性肾病足细胞中的表达是否可以作为不可逆足细胞疾病的预后因素。这可能有助于深入了解UCH-L1在足细胞损伤的发生和发展中可能的病理作用。在第三部分中，我们将分析UCH-L1在免疫介导的肾损伤中的作用。初步数据显示，UCH-L1在小鼠肾脏树突状细胞中表达，在用肾毒性血清治疗的构成UCH-L1小鼠中，免疫反应发生改变。我们将建立树突状细胞特异性UCH-L1缺陷小鼠，并在肾毒性肾炎模型中分析其免疫应答和临床转归。

Ubiquitin C-terminal hydrolase-L1 (UCH-L1) is a key player of the ubiquitin system through the generation and stabilization of monomeric ubiquitin. Previously we were able to demonstrate in cell culture experiments, in vivo experiments and human glomerulopathies that UCH-L1 regulates the ubiquitin homeostasis in podocytes during glomerular disease. In a first part we want to analyse the exact functions of UCH-L1 in podocyte injury. Therefore, we generated podocyte selective UCH-L1 gene-deficient mice to induce an immunologic and a toxic model of podocyte damage and to subsequently assess clinical and morphological parameters of podocyte injury. Biochemical effects of UCH-L1 deficiency and mutations will be analysed in podocyte cell culture experiments. In a second part we will assess whether UCH-L1 expression in podocytes in human membranous nephropathy could serve as a prognostic factor for irreversible podocyte disease. This might help to gain insight into the possible pathologic role of UCH-L1 in the generation and progression of podocyte injury. In a third part we will analyse the role of UCH-L1 in immune mediated renal injury. Preliminary data demonstrate an UCH-L1 expression in murine kidney dendritic cells and an altered immune response in constitutive UCH-L1 mice treated with nephrotoxic serum. We will generate dendritic cell specific UCH-L1 deficient mice and analyse the immune response and clinical outcome in the model of nephrotoxic nephritis.