Role of Ubiquitin C-Terminal Hydrolase-L1 in Glomerulonephritis

泛素c端水解酶- l1 （UCH-L1）是泛素系统的关键分子，通过生成和稳定单体泛素。以前，我们能够在细胞培养实验、体内实验和人类肾小球疾病中证明UCH-L1调节肾小球疾病期间足细胞中的泛素稳态。在第一部分中，我们想分析UCH-L1在足细胞损伤中的确切功能。因此，我们制造了足细胞选择性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分析。在第二部分，我们将评估UCH-L1在人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在足细胞损伤发生和进展中的可能病理作用。在第三部分，我们将分析UCH-L1在免疫介导的肾损伤中的作用。初步数据表明，UCH-L1在小鼠肾树突状细胞中表达，并且在肾毒性血清处理的组成型UCH-L1小鼠中免疫反应发生改变。我们将生成树突状细胞特异性UCH-L1缺陷小鼠，并分析肾毒性肾炎模型的免疫反应和临床结果。

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.