Xenopus Bicaudal-C a Model for Polycystic Kidney Disease

描述（由申请人提供）：多囊肾病（PKD）是终末期肾衰竭的主要原因，需要广泛的治疗，如透析和肾移植。由于肾囊肿形成的分子机制尚不清楚，目前只有有限的PKD治疗形式。多年来，在鉴定人类形式PKD的突变基因和开发动物模型以研究这些有害疾病的发病机制方面取得了相当大的进展。除了分析小鼠和大鼠PKD模型外，研究更原始的肾原肾已成为研究PKD的另一种选择。原肾的简单性和快速发展为研究上皮畸形导致PKD的分子机制提供了一个非常有吸引力的模型。使用morpholino反义寡聚物的功能丧失研究提供了一种快速简便的方法，可以在数周内分析基因功能，而不是在小鼠中进行相当缓慢的遗传操作。这有助于对PKD期间肾脏发育及其扰动进行更探索性的研究。

DESCRIPTION (provided by applicant): Polycystic Kidney Diseases (PKD) are the leading cause of end-stage renal failure and require extensive treatments, such as dialysis and kidney transplantation. Only limited forms of therapy for PKD exist, since the molecular mechanism underlying the formation of renal cysts is still poorly understood. Over the years considerable progress has been made in identifying genes mutated in human forms of PKD and in the development of animal models to study the pathogenesis of these detrimental diseases. Besides the analysis of mouse and rat PKD models, the study of the more primitive pronephric kidney has emerged as an alternative to studying PKD. The simplicity and the rapid development of the pronephros is a very attractive model to study the molecular mechanism underlying the epithelial malformations causing PKD. Loss-of-function studies using morpholino antisense oligomers provide a fast and easy way to analyze gene function within weeks instead of the rather slow genetic manipulations in mouse. This facilitates a more exploratory approach towards kidney development and its perturbation during PKD. This proposal studies Bicaudal-C, a gene mutated in the bpk and jcpk mouse models of PKD. In a previous study, the function of the Xenopus homologue of Bicaudal-C during germ layer patterning was analyzed. Here, we propose to study the role of Bicaudal-C during pronephros development in the amphibian, Xenopus laevis, by eliminating the protein in the pronephros using antisense morpholino oligomers. We will test the hypothesis that loss-of-Bicaudal-C in the pronephros induces epithelial abnormalities similar to those described in human and mouse PKD. Molecular markers will be used to characterize the onset and the progression of the phenotype. The study will also test whether elimination of Bicaudal-C leads to defects in the function of the primary cilia present on renal epithelial cells. The results will provide novel insights into PKD and will be directly applicable to mammalian studies of PKD. Furthermore, this study will provide the basis for future studies of PKD in Xenopus, using the fast developing amphibian model system to characterize the underlying biological and biochemical pathways leading to PKD.