Xenopus Bicaudal-C a Model for Polycystic Kidney Disease

描述(申请人提供)：多囊肾疾病(PKD)是终末期肾功能衰竭的主要原因，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仍然知之甚少，目前对PKD的治疗形式有限。多年来，在鉴定人类形式的PKD突变基因以及研究这些有害疾病的发病机制的动物模型方面取得了相当大的进展。除了对小鼠和大鼠PKD模型的分析外，对更原始的前肾的研究已经成为研究PKD的一种选择。前肾的简单和快速发育是研究上皮畸形导致PKD的分子机制的一个非常有吸引力的模型。使用吗啡反义寡聚体的功能丧失研究提供了一种快速而简单的方法，可以在几周内分析基因功能，而不是在小鼠身上进行相当缓慢的遗传操作。这有助于对肾脏发育及其在PKD期间的扰动采取更具探索性的方法。 这项建议研究了Bicaudal-C基因，这是一种在PKD的bpk和jcpk小鼠模型中突变的基因。在先前的研究中，分析了Bicaudal-C的非洲爪哇同系物在胚层构图过程中的功能。在这里，我们建议通过使用反义吗啉低聚物消除前肾中的蛋白质来研究Bicaudal-C在两栖动物非洲爪哇前肾发育中的作用。我们将检验这样一种假设，即前肾中双尾C的缺失会导致与人类和小鼠PKD中描述的类似的上皮异常。分子标记将被用来表征表型的开始和发展。这项研究还将测试双尾C的消除是否会导致肾上皮细胞上存在的初级纤毛的功能缺陷。这些结果将为PKD提供新的见解，并将直接适用于哺乳动物对PKD的研究。此外，本研究还将利用快速发展的两栖动物模型系统来描述导致非洲爪哇PKD的潜在生物学和生化途径，从而为未来非洲爪哇PKD的研究提供基础。

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.