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: 7287296
• 负责人: Oliver Wessely
• 金额: $ 14.2万
• 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 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7287296
• 关键词: Address; Adult; Amphibia; Animal Model; Anterior; Autosomal Dominant Polycystic Kidney; Autosomal Recessive Polycystic Kidney; Biochemical Pathway; Biological; Biological Markers; Biological Models; Biological Process; Cells; Child; Chronic Kidney Failure; Cilia; Companions; Cues; Cyst; Cystic kidney; Defect; Development; Dialysis procedure; Disease; Disease model; Drosophila genus; Embryo; Embryonic Development; End stage renal failure; Endoderm; Epithelial; Epithelial Cells; Epithelium; Future; Genes; Genetic; Germ Layers; Hereditary Disease; Homologous Gene; Hour; Human; Individual; Inherited; Kidney; Kidney Transplantation; Lead; Liquid substance; Localized; Mesonephric structure; Messenger RNA; Metanephric structure; Microinjections; Modeling; Molecular; Mus; Mutate; Mutation; Nephrons; Organogenesis; Pathogenesis; Pattern; Phenotype; Physical Dialysis; Plasmids; Polycystic Kidney Diseases; Pronephric structure; Proteins; RNA Binding; Rattus; Research; Role; System; Testing; Thinking; Time; Tubular formation; Week; Xenopus; Xenopus laevis; base; citrate carrier; gene function; genetic manipulation; insight; loss of function; malformation; mouse model; nephrogenesis; novel

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）：多囊性肾脏疾病（PKD）是终末期肾衰竭的主要原因，需要广泛的治疗方法，例如透析和肾脏移植。仅存在有限的PKD治疗形式，因为肾囊肿形成的分子机制仍然很少了解。多年来，在识别以人类形式的PKD和动物模型发展以研究这些有害疾病的发病机理的基因方面取得了很大进展。除了对小鼠和大鼠PKD模型的分析外，对更原始的促脑肾脏的研究已成为研究PKD的替代方法。脑力脑的简单性和快速发展是一个非常有吸引力的模型，用于研究引起PKD的上皮畸形的分子机制。使用吗啡反义寡聚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，而不是小鼠中相当缓慢的遗传操作来分析基因功能。这有助于在PKD期间采用更探索性的肾脏发育及其扰动方法。 该建议研究Bicauaudal-C，一种在PKD的BPK和JCPK小鼠模型中突变的基因。在先前的一项研究中，分析了生殖层模式期间双尾caudapus同源物的功能。在这里，我们建议通过使用反义莫诺夫洛利诺寡聚体消除两栖动物Xenopus laevis在两栖动物Xenopus laevis中的作用。我们将检验以下假设：近脑中的杀伤症损失会引起与人和小鼠PKD中所述的上皮异常。分子标记将用于表征表型的发作和进展。该研究还将测试消除双毛-C是否会导致肾上皮细胞上原发性纤毛的功能缺陷。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，这项研究将使用快速开发的两栖动物模型系统为未来的PKD研究提供基础，以表征导致PKD的基本生物学和生化途径。