The Role of Bicaudal-C in Polycystic Kidney Disease

Bicaudal-C 在多囊肾病中的作用

• 批准号: 8529504
• 负责人: Oliver Wessely
• 金额: $ 32.3万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-21 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8529504
• 关键词: 3' Untranslated Regions; Address; Adult; Amphibia; Anterior; Autosomal Dominant Polycystic Kidney; Autosomal Recessive Polycystic Kidney; Basic Science; Binding; Binding Sites; Biochemical Pathway; Biogenesis; Biological; Biological Models; Caenorhabditis elegans; Cell division; Cells; Child; Chronic Kidney Failure; Companions; Cyst; Cystic kidney; Data; Defect; Development; Dialysis procedure; Disease; Disease Progression; Disease model; Drosophila genus; Drug Formulations; Elements; Embryo; End stage renal failure; Epithelial; Future; Genes; Health; Hereditary Disease; Homologous Gene; Human; Inherited; Kidney; Kidney Transplantation; Length; Liquid substance; Messenger RNA; Metanephric structure; MicroRNAs; Modeling; Molecular; Mus; Mutant Strains Mice; Mutate; Mutation; Nephrons; Organism; PKD2 protein; Pathogenesis; Pattern; Phenotype; Polycystic Kidney Diseases; Pronephric structure; Proteins; RNA Binding; Rattus; Regulation; Regulator Genes; Role; Site; System; Testing; Therapeutic Intervention; Xenopus; Zebrafish; animal model development; base; citrate carrier; clinical application; disease phenotype; genetic analysis; homologous recombination; insight; loss of function; malformation; mouse model; nephrogenesis; novel; polycystic kidney disease 1 protein; prevent; protein expression

DESCRIPTION (provided by applicant): Polycystic Kidney Diseases (PKD) are the leading cause of end-stage renal failure and are characterized by the development of renal cysts along the entire length of the nephron. They require extensive treatments, such as dialysis and kidney transplantation. Only limited forms of therapy for PKD exist, since the molecular mechanisms underlying the formation of renal cysts are 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 mouse and rat PKD models, the more primitive pronephric kidney of Xenopus or zebrafish has emerged as an alternative model system to study the molecular mechanisms underlying the epithelial malformations causing PKD. With its fast development and ease of molecular manipulations, the pronephric kidney is an ideal companion system to the study of PKD in humans or mice. In this proposal we will use the mouse metanephros and the amphibian pronephros to study the RNA binding molecule Bicaudal-C. Mice lacking Bicaudal-C protein develop renal cysts as early as embryonic day 15.5. Cyst formation is first detected in the glomerulus, but can later be detected along the entire length of the nephron. Similarly, in Xenopus, loss-of-Bicaudal-C induces a "PKD-like" phenotype in the pronephros. Importantly, the molecular mechanism of Bicaudal-C activity in kidney development and its connection to the genes mutated in human PKD, i.e. Polycystin-1, Polycystin-2 and Polyductin/Fibrocystin is still not understood. This proposal will address these questions. We will test the hypothesis that Bicaudal-C is a translational regulator of genes involved in Polycystic Kidney Disease. It is based on four observations: (1) Bicaudal-C mutant mice have reduced Polycystin-2 mRNA and protein levels before the onset of cyst formation. (2) The regulation of Polycystin-2 is posttranscriptional. (3) Bicaudal-C protein is localized to P-Bodies and has been shown in Drosophila and C. elegans to regulate a selected group of mRNAs at the posttranscriptional level. (4) Many PKD genes have evolutionary conserved miRNA binding sites in their 3' UTR. If successful, this study will provide novel insights to the underlying biological and biochemical pathways leading to the renal cyst formation in PKD. It will integrate one of the least understood PKD genes into the existing paradigms of PKD. As such, it will be directly applicable to future studies of PKD and may provide a new angle for therapeutic interventions.

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，其特征是沿着肾单位的整个长度出现肾囊肿。他们需要广泛的治疗，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 的治疗方法有限。多年来，在识别人类 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。除了小鼠和大鼠 PKD 模型外，更原始的爪蟾或斑马鱼的前肾已成为研究导致 PKD 的上皮畸形分子机制的替代模型系统。由于其快速发展和易于分子操作，原肾是研究人类或小鼠 PKD 的理想伴侣系统。在本提案中，我们将使用小鼠后肾和两栖动物前肾来研究 RNA 结合分子 Bicaudal-C。缺乏 Bicaudal-C 蛋白的小鼠早在胚胎第 15.5 天就会出现肾囊肿。首先在肾小球中检测到囊肿形成，但随后可以沿着肾单位的整个长度检测到。类似地，在非洲爪蟾中，Bicaudal-C 的缺失会在前肾中诱导“PKD 样”表型。重要的是，肾脏发育中 Bicaudal-C 活性的分子机制及其与人类 PKD 突变基因（即多囊蛋白-1、多囊蛋白-2 和多囊蛋白/纤维囊蛋白）的联系仍不清楚。本提案将解决这些问题。我们将检验 Bicaudal-C 是多囊肾相关基因的翻译调节因子的假设。它基于四个观察结果：(1) Bicaudal-C 突变小鼠在囊肿形成开始前降低了多囊蛋白 2 mRNA 和蛋白质水平。 (2) Polycystin-2的调节是转录后的。 (3) Bicaudal-C 蛋白定位于 P-Bodies，并已在果蝇和秀丽隐杆线虫中显示出在转录后水平调节一组选定的 mRNA。 (4) 许多 PKD 基因在其 3' UTR 中具有进化保守的 miRNA 结合位点。如果成功，这项研究将为 PKD 中导致肾囊肿形成的潜在生物学和生化途径提供新的见解。它将把人们最不了解的 PKD 基因之一整合到现有的 PKD 范式中。因此，它将直接适用于 PKD 的未来研究，并可能为治疗干预提供新的角度。