Xenopus Bicaudal-C a Model for Polycystic Kidney Disease

非洲爪蟾双尾-C 多囊肾病模型

• 批准号: 6901574
• 负责人: Oliver Wessely
• 金额: $ 14.3万
• 依托单位: LSU HEALTH SCIENCES CENTER
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-06-01 至 2007-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6901574
• 关键词: Xenopus; antisense nucleic acid; cilium; developmental genetics; disease /disorder model; epithelium; nephrogenesis; nonmammalian vertebrate embryology; polycystic kidney

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.

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，例如透析和肾移植。由于肾囊肿形成的分子机制仍知之甚少，因此目前针对 PKD 的治疗方式有限。多年来，在鉴定人类 PKD 中的突变基因以及开发动物模型来研究这些有害疾病的发病机制方面，已经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成为研究 PKD 的替代方法。前肾的简单性和快速发育是研究引起 PKD 的上皮畸形分子机制的一个非常有吸引力的模型。使用吗啉代反义寡聚物进行功能丧失研究提供了一种在几周内分析基因功能的快速简便的方法，而不是在小鼠中进行相当缓慢的基因操作。这有助于对 PKD 期间肾脏发育及其扰动采取更具探索性的方法。 该提案研究 Bicaudal-C，这是一种在 PKD 的 bpk 和 jcpk 小鼠模型中突变的基因。在之前的一项研究中，分析了 Bicaudal-C 的爪蟾同源物在胚层图案形成过程中的功能。在这里，我们建议通过使用反义吗啉寡聚物消除前肾中的蛋白质来研究 Bicaudal-C 在两栖动物非洲爪蟾前肾发育过程中的作用。我们将检验以下假设：前肾中 Bicaudal-C 的缺失会引起与人类和小鼠 PKD 中描述的类似的上皮异常。分子标记将用于表征表型的发生和进展。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的功能缺陷。研究结果将为多囊肾提供新的见解，并将直接应用于多囊肾的哺乳动物研究。此外，这项研究将为未来爪蟾多囊肾的研究提供基础，利用快速发展的两栖动物模型系统来表征导致多囊肾的潜在生物学和生化途径。