The Role of Cdk5 in Podocyte Biology

肾小球疾病是慢性和终末期肾衰竭的主要原因。终末分化和高度特化的肾小球上皮细胞，足细胞，是肾小球滤过屏障的关键组成部分，并且是正常肾小球完整性所必需的。由于细胞凋亡和细胞从肾小球基底膜（GBM）脱离导致足细胞的损失有助于导致蛋白尿和肾小球硬化的肾脏疾病的发展。因此，了解确定足细胞功能和存活的调节机制是非常重要的。我们已经表明，p35和细胞周期蛋白I介导的细胞周期蛋白依赖性激酶（Cdk）5活性是后天性损伤后足细胞存活的关键。Cdk5是一种非典型的Cdk，不参与细胞周期调控，而是控制细胞分化。在这个项目中，我们将（i）研究Cdk5如何调节肾小球生物学，（ii）确定Cdk5通路的组成部分，并表征所涉及的信号网络的监管原则，（iii）解开非典型细胞周期蛋白依赖性激酶在肾脏疾病发病机制中的作用。我们期望我们的研究结果将导致更好地了解一大群肾小球疾病，其特征是蛋白尿和肾衰竭的发展。

Glomerular diseases are a leading cause of chronic and end stage kidney failure. The terminally differentiated and highly specialized glomerular epithelial cell, the podocyte, is a critical component of the glomerular filtration barrier, and required for normal glomerular integrity. Loss of podocytes due to apoptosis and detachment of the cells from the glomerular basement membrane (GBM) contributes to the development of kidney diseases resulting in proteinuria and glomerulosclerosis. Thus, understanding regulatory mechanisms ascertaining podocyte function and survival is of major importance. We have shown that both, p35 and cyclin I mediated cyclin dependent kinase (Cdk) 5 activity is crucial for podocyte survival following acquired injury. Cdk5 is an atypical Cdk that is not involved in cell cycle regulation but rather controls cellular differentiation. In this project we will (i) investigate how Cdk5 regulates glomerular biology, (ii) identify components of the Cdk5 pathway and characterize regulatory principles of the signalling network involved and (iii) unravel the role of atypical cyclin-dependent kinases in the pathogenesis of renal diseases. We expect that our results will lead to a better understanding of a large group of glomerular disorders that is characterized by the development of proteinuria and kidney failure.