The Role of Bicaudal-C in Polycystic Kidney Disease

Bicaudal-C 在多囊肾病中的作用

• 批准号: 8332924
• 负责人: Oliver Wessely
• 金额: $ 33.47万
• 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 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8332924
• 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. PUBLIC HEALTH RELEVANCE: Polycystic Kidney Diseases are very prevalent, genetic disorders characterized by the formation of fluid-filled cysts in the kidney. This project studies the RNA-binding molecule Bicaudal-C, its molecular mechanism and its connection to those genes mutated in humans forms of Polycystic Kidney Disease. This study will provide new insides into disease progression and novel angles for therapeutic intervention.

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，其特征是肾囊肿沿着整个肾单位的长度发展。他们需要广泛的治疗，如透析和肾移植。由于肾囊肿形成的分子机制尚不清楚，目前只有有限的PKD治疗形式。多年来，在鉴定人类形式PKD的突变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。除了小鼠和大鼠PKD模型外，爪蟾或斑马鱼更原始的肾原肾已成为研究上皮畸形导致PKD的分子机制的另一种模型系统。由于其快速发展和易于分子操作，肾原肾是研究人类或小鼠PKD的理想伴侣系统。本研究将利用小鼠后肾和两栖动物前肾对RNA结合分子Bicaudal-C进行研究。缺乏Bicaudal-C蛋白的小鼠早在胚胎15.5天就出现肾囊肿。囊肿的形成首先在肾小球中被发现，但后来可以沿着整个肾元的长度被发现。同样地，在非洲爪蟾中，失去双头神经c会导致前肾出现“pkd样”表型。重要的是，Bicaudal-C活性在肾脏发育中的分子机制及其与人类PKD中突变基因（polycytin -1， polycytin -2和Polyductin/Fibrocystin）的联系尚不清楚。这项建议将解决这些问题。我们将检验Bicaudal-C是多囊肾病相关基因的翻译调节因子的假设。这是基于四个观察结果：(1)Bicaudal-C突变小鼠在囊肿形成开始前，polycytin -2 mRNA和蛋白水平降低。(2)多囊蛋白-2的调控是转录后的。(3) Bicaudal-C蛋白定位于p -小体，并在果蝇和秀丽隐杆线虫中被证明在转录后水平调控一组选定的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。它将把一个最不为人所知的PKD基因整合到PKD的现有范式中。因此，它将直接适用于未来PKD的研究，并可能为治疗干预提供新的角度。公共卫生相关性：多囊肾病是一种非常普遍的遗传性疾病，其特征是在肾脏中形成充满液体的囊肿。本项目研究rna结合分子Bicaudal-C，其分子机制及其与人类多囊肾病中突变基因的联系。该研究将为疾病进展提供新的视角，并为治疗干预提供新的角度。