Xenopus Bicaudal-C a Model for Polycystic Kidney Disease

描述（由申请人提供）：多囊肾疾病（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。由于对肾囊肿形成的分子机制仍知之甚少，因此PKD的治疗形式有限。多年来，在鉴定人类形式的PKD中突变的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。除了对小鼠和大鼠PKD模型的分析之外，对更原始的前肾的研究已经成为研究PKD的替代方案。原肾结构简单，发育迅速，是研究PKD上皮畸形分子机制的理想模型。使用吗啉代反义寡聚体的功能丧失研究提供了一种快速简便的方法，可以在几周内分析基因功能，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。 该提案研究Bicaudal-C，一种在PKD的bpk和jcpk小鼠模型中突变的基因。在以前的研究中，非洲爪蟾同源Bicaudal-C在胚层图案的功能进行了分析。在这里，我们建议研究的作用，Bicaudal-C在前肾发育中的两栖动物，非洲爪蟾，通过消除蛋白质的前肾使用反义吗啉寡聚体。我们将检验这一假设，即双尾-C在原肾中的缺失诱导了与人类和小鼠PKD中描述的相似的上皮异常。将使用分子标志物来表征表型的发作和进展。该研究还将测试Bicaudal-C的消除是否会导致肾上皮细胞上初级纤毛功能的缺陷。这些结果将为PKD提供新的见解，并将直接适用于PKD的哺乳动物研究。此外，这项研究将为今后的研究提供基础，在非洲爪蟾PKD，使用快速发展的两栖动物模型系统，以表征潜在的生物和生化途径，导致PKD。

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.